VCV000417619.1 - ClinVar

NM_001386393.1(PANK2):c.1096_1099del (p.Met366fs)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(1)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

no assertion criteria provided

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001386393.1(PANK2):c.1096_1099del (p.Met366fs)

Variation ID: 417619 Accession: VCV000417619.1

Type and length

Deletion, 4 bp

Location

Cytogenetic: 20p13 20: 3916940-3916943 (GRCh38) [ NCBI UCSC ] 20: 3897587-3897590 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 13, 2018	Feb 13, 2018	Nov 5, 2016

HGVS

Nucleotide	Protein	Molecular consequence
NM_001386393.1:c.1096_1099del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001373322.1:p.Met366fs	frameshift
NM_001324191.2:c.553_556del	NP_001311120.1:p.Met185fs	frameshift
NM_001324193.2:c.118_121del	NP_001311122.1:p.Met40fs	frameshift
NM_024960.6:c.553_556del	NP_079236.3:p.Met185fs	frameshift
NM_153638.3:c.1426_1429delATGA
NM_153638.4:c.1426_1429del	NP_705902.2:p.Met476fs	frameshift
NM_153640.4:c.553_556del	NP_705904.1:p.Met185fs	frameshift
NR_136715.2:n.997_1000del		non-coding transcript variant
NC_000020.11:g.3916940_3916943del
NC_000020.10:g.3897587_3897590del
NG_008131.3:g.33102_33105del
LRG_1016:g.33102_33105del
LRG_1016t1:c.1426_1429del	LRG_1016p1:p.Met476fs
LRG_1016t2:c.1096_1099del	LRG_1016p2:p.Met366fs

... more HGVS ... less HGVS

Protein change

M185fs, M40fs, M476fs, M366fs

Other names

Canonical SPDI

NC_000020.11:3916939:ATGA:

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

protein truncation; Variation Ontology [ VariO:0015]

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA658684233 dbSNP: rs1555789557 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PANK2		-	-	GRCh38 GRCh37	481	748

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Pigmentary pallidal degeneration	Pathogenic (1)	no assertion criteria provided	Nov 5, 2016	RCV000578477.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Nov 05, 2016)	no assertion criteria provided Method: research	Pigmentary pallidal degeneration (Autosomal recessive inheritance) Affected status: not applicable Allele origin: not applicable	Dr. Faghihi's Medical Genetic Center Accession: SCV000537313.1 First in ClinVar: Feb 13, 2018 Last updated: Feb 13, 2018	Publications: PubMed (1) PubMed: 28821231 Comment: An 8 years old Iranian girl was admitted to Namazi Hospital (Shiraz, Iran) in 2015 with clinical diagnosis of dystonia who was apparently normal before … (more) An 8 years old Iranian girl was admitted to Namazi Hospital (Shiraz, Iran) in 2015 with clinical diagnosis of dystonia who was apparently normal before the age of 4. She developed bone fracture, muscle rigidity, abnormal movement, lack of coordination, chorea, and dystonia with seizure attacks. She was intellectually normal but she had speech problem due to medications she was taking which were Sirdalud (Tizanidine), Gabax, trihexidine and NA Valporate. Multiplanar multisequential MRI images through the brain with usual protocol were taken which demonstrated normal signal intensity of both cerebral hemispheres with no sign of mass or hemorrhage or ischemic infarction. No hydrocephalus or shift of midline structure was found. Posterior fossa structures including cerebral hemispheres showed normal signal intensity without any mass or hemorrhage or ischemic infarction. 7the-8the nerve root complexes appeared normal and pituitary gland was also normal with no sign of gross mass. No extra-axial mass or hematoma or fluid collection was observed. It is worth noting that generalized cortical atrophy was considerable which was more than that of expected for the patientâ€™s age. Mucosal thickening was noted at both ethmoidal maxillary sinuses due to sinusitis. Mild inflammatory change at right mastoid air cells and the â€˜â€˜eye-of-the-tigerâ€™â€™ sign in MRI imaging was remarkable (figure 1). But, M.R.I of the cervical spine without contrast showed normal features. Paraclinical examinations were also requested which showed increased level of alkaline phosphatase (ALP) (191 U/L) and creatine phosphokinase (CPK) (456 U/L). (less) Sex: female Comment on evidence: Whole Exome sequencing using Next Generation Illumina Sequencing was used to enrich all exons of protein-coding genes as well as some important other genomic regions … (more) Whole Exome sequencing using Next Generation Illumina Sequencing was used to enrich all exons of protein-coding genes as well as some important other genomic regions in these two affected patients. A deleterious homozygous four-nucleotide deletion causing frameshift deletion in PANK2 gene (c.1426_1429delATGA, p.M476fs) was identified in an 8 years old girl with dystonia, bone fracture, muscle rigidity, abnormal movement, lack of coordination and chorea. The identified novel mutation were also confirmed by Sanger sequencing in the proband and their parents. (less) Method: Whole Exome Sequencing was utilized for amplification and sequencing of all exons of protein-coding genes as well as some important other genomic regions. The DNA samples were sequenced, using Illumina HiSeq2000 machine and standard Illumina protocol for pair-end 99-nucleotide sequencing. Detail of sample alignment is listed below in Table 1. Briefly, next generation sequencing was performed to sequence close to 100 million reads on Illumina HiSeq2000 Sequencer. In general, test platform examined >95% of the targeted regions with sensitivity of above 99%. In this test, point mutations and micro-insertion/deletions and duplication (<20bp) can be simultaneously detected. Bioinformatics analysis of the sequencing results was performed using BWA aligner [35], GATK [36] and annovar [37] open access software as well as public databases and standard bioinformatics software. Sanger sequencing and segregation studies: Whole blood samples were collected in EDTA tubes from family members of the proband and then genomic DNA was extracted from the peripheral blood lymphocytes by QIAamp DNA Blood Mini Kit (Germany) according to the manufacturer's instructions. After that, the genomic DNA concentration was measured by NanoDrop (ND1000, USA) and stored at âˆ’20 Â°C until use. To conï¬rm the novel identified mutation, PCR was performed for the proband and her parents (PCR condition are given in table 2) and amplified DNA was then subjected to Sanger Sequencing using both forward and reverse primers according to ABI BigDye Terminator Cycle Sequencing Kit (Applied BiosystemsÂ®, USA). Sanger sequencing data was analyzed using NCBI BLAST and CodonCode Aligner software. Multiple sequence alignment analysis extracted from Polyphen website was also used to compare the amino acid sequence of human PANK2 protein with corresponding proteins across all Kingdoms. Following bioinformatics software and websites were also used to identify the features of PANK2 and the consequences of mutation in the given position of the protein: Polyphen, Mutation Taster, SIFT, and DISOPRED3 (Intrinsic disorder predictor).

Comment:

An 8 years old Iranian girl was admitted to Namazi Hospital (Shiraz, Iran) in 2015 with clinical diagnosis of dystonia who was apparently normal before the age of 4. She developed bone fracture, muscle rigidity, abnormal movement, lack of coordination, chorea, and dystonia with seizure attacks. She was intellectually normal but she had speech problem due to medications she was taking which were Sirdalud (Tizanidine), Gabax, trihexidine and NA Valporate. Multiplanar multisequential MRI images through the brain with usual protocol were taken which demonstrated normal signal intensity of both cerebral hemispheres with no sign of mass or hemorrhage or ischemic infarction. No hydrocephalus or shift of midline structure was found. Posterior fossa structures including cerebral hemispheres showed normal signal intensity without any mass or hemorrhage or ischemic infarction. 7the-8the nerve root complexes appeared normal and pituitary gland was also normal with no sign of gross mass. No extra-axial mass or hematoma or fluid collection was observed. It is worth noting that generalized cortical atrophy was considerable which was more than that of expected for the patientâ€™s age. Mucosal thickening was noted at both ethmoidal maxillary sinuses due to sinusitis. Mild inflammatory change at right mastoid air cells and the â€˜â€˜eye-of-the-tigerâ€™â€™ sign in MRI imaging was remarkable (figure 1). But, M.R.I of the cervical spine without contrast showed normal features. Paraclinical examinations were also requested which showed increased level of alkaline phosphatase (ALP) (191 U/L) and creatine phosphokinase (CPK) (456 U/L).

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
protein truncation (VariO:0015)	Whole Exome Sequencing was utilized for amplification and sequencing of all exons of protein-coding genes as well as some important other genomic regions. The DNA samples were sequenced, using Illumina HiSeq2000 machine and standard Illumina protocol for pair-end 99-nucleotide sequencing. Detail of sample alignment is listed below in Table 1. Briefly, next generation sequencing was performed to sequence close to 100 million reads on Illumina HiSeq2000 Sequencer. In general, test platform examined >95% of the targeted regions with sensitivity of above 99%. In this test, point mutations and micro-insertion/deletions and duplication (<20bp) can be simultaneously detected. Bioinformatics analysis of the sequencing results was performed using BWA aligner [35], GATK [36] and annovar [37] open access software as well as public databases and standard bioinformatics software. Sanger sequencing and segregation studies: Whole blood samples were collected in EDTA tubes from family members of the proband and then genomic DNA was extracted from the peripheral blood lymphocytes by QIAamp DNA Blood Mini Kit (Germany) according to the manufacturer's instructions. After that, the genomic DNA concentration was measured by NanoDrop (ND1000, USA) and stored at âˆ’20 Â°C until use. To conï¬rm the novel identified mutation, PCR was performed for the proband and her parents (PCR condition are given in table 2) and amplified DNA was then subjected to Sanger Sequencing using both forward and reverse primers according to ABI BigDye Terminator Cycle Sequencing Kit (Applied BiosystemsÂ®, USA). Sanger sequencing data was analyzed using NCBI BLAST and CodonCode Aligner software. Multiple sequence alignment analysis extracted from Polyphen website was also used to compare the amino acid sequence of human PANK2 protein with corresponding proteins across all Kingdoms. Following bioinformatics software and websites were also used to identify the features of PANK2 and the consequences of mutation in the given position of the protein: Polyphen, Mutation Taster, SIFT, and DISOPRED3 (Intrinsic disorder predictor).	Result not provided	Dr. Faghihi's Medical Genetic Center Accession: SCV000537313.1	Publications PubMed (1)

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Novel mutations in PANK2 and PLA2G6 genes in patients with neurodegenerative disorders: two case reports.	Dastsooz H	BMC medical genetics	2017	PMID: 28821231

Text-mined citations for rs1555789557 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jun 23, 2024

ClinVar Genomic variation as it relates to human health

NM_001386393.1(PANK2):c.1096_1099del (p.Met366fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1555789557 ...