VCV000434550.9 - ClinVar

NM_031448.6(C19orf12):c.161-2del

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.

(3)

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.

Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_031448.6(C19orf12):c.161-2del

Variation ID: 434550 Accession: VCV000434550.9

Type and length

Deletion, 1 bp

Location

Cytogenetic: 19q12 19: 29702979 (GRCh38) [ NCBI UCSC ] 19: 30193886 (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	Aug 28, 2017	Feb 20, 2024	Sep 27, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_031448.6:c.161-2del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NM_001031726.3:c.194-2delA
NM_001031726.4:c.161-2del		splice acceptor
NM_001256046.3:c.161-2del		splice acceptor
NM_001256047.2:c.161-2del		splice acceptor
NM_001282929.1:c.-32-2del		splice acceptor
NM_001282930.3:c.-32-2del		splice acceptor
NM_001282931.3:c.-32-2del		splice acceptor
NC_000019.10:g.29702979del
NC_000019.9:g.30193886del
NG_031970.2:g.17811del

... more HGVS ... less HGVS

Protein change

Other names

NP_001026896.2:p.G66_G73del

Canonical SPDI

NC_000019.10:29702978:T:

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

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.

The Genome Aggregation Database (gnomAD), exomes 0.00001

Links

ClinGen: CA632143698 dbSNP: rs1352744778 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.
C19orf12		-	-	GRCh38 GRCh37	282	323

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.
Neurodegeneration with brain iron accumulation 4	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Sep 1, 2022	RCV000503280.7
Hereditary spastic paraplegia 43	Uncertain significance (1)	criteria provided, single submitter	Sep 27, 2022	RCV002527210.3

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 (Aug 26, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurodegeneration with brain iron accumulation 4 Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000593800.1 First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017
Likely pathogenic (Sep 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurodegeneration with brain iron accumulation 4 Affected status: yes Allele origin: germline	3billion Accession: SCV002573259.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Publications: PubMed (1) PubMed: 29915382 Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Canonical splice site is predicted to alter … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Canonical splice site is predicted to alter splicing and result in a loss or disruption of normal protein function. The predicted truncated protein may be shortened by more than 10%. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with C19orf12-related disorder (ClinVar ID: VCV000434550 / PMID: 29915382). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Gait disturbance (present) , Ankle flexion contracture (present) , Muscle weakness (present) , Slurred speech (present) , Muscular atrophy (present) , EMG abnormality (present) , … (more) Gait disturbance (present) , Ankle flexion contracture (present) , Muscle weakness (present) , Slurred speech (present) , Muscular atrophy (present) , EMG abnormality (present) , Pes cavus (present) , Fatigue (present) , Tremor (present) (less)
Uncertain significance (Sep 27, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary spastic paraplegia 43 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003472698.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024	Publications: PubMed (4) PubMed: 17576681‚ 9536098‚ 23269600‚ 29915382 Comment: In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant … (more) In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 434550). This variant has been observed in individuals with clinical features of autosomal recessive neurodegeneration with brain iron accumulation (PMID: 23269600, 29915382). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change falls in intron 2 of the C19orf12 gene. It does not directly change the encoded amino acid sequence of the C19orf12 protein. It affects a nucleotide within the consensus splice site. (less)

Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Canonical splice site is predicted to alter splicing and result in a loss or disruption of normal protein function. The predicted truncated protein may be shortened by more than 10%. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with C19orf12-related disorder (ClinVar ID: VCV000434550 / PMID: 29915382). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 434550). This variant has been observed in individuals with clinical features of autosomal recessive neurodegeneration with brain iron accumulation (PMID: 23269600, 29915382). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change falls in intron 2 of the C19orf12 gene. It does not directly change the encoded amino acid sequence of the C19orf12 protein. It affects a nucleotide within the consensus splice site.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Targeted exome analysis identifies the genetic basis of disease in over 50% of patients with a wide range of ataxia-related phenotypes.	Sun M	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 29915382
New NBIA subtype: genetic, clinical, pathologic, and radiographic features of MPAN.	Hogarth P	Neurology	2013	PMID: 23269600
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.	Buratti E	Nucleic acids research	2007	PMID: 17576681
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098

Text-mined citations for rs1352744778 ...

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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_031448.6(C19orf12):c.161-2del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1352744778 ...