NM_007254.4(PNKP):c.1448+2T>A AND Developmental and epileptic encephalopathy, 12

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 9, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002035465.4

Allele description [Variation Report for NM_007254.4(PNKP):c.1448+2T>A]

NM_007254.4(PNKP):c.1448+2T>A

Gene:

PNKP:polynucleotide kinase 3'-phosphatase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19q13.33

Genomic location:

Preferred name:

NM_007254.4(PNKP):c.1448+2T>A

HGVS:

NC_000019.10:g.49861447A>T
NG_027717.1:g.11119T>A
NG_050666.1:g.17604A>T
NM_007254.4:c.1448+2T>AMANE SELECT
NC_000019.9:g.50364704A>T

Links:

dbSNP: rs1600414549

NCBI 1000 Genomes Browser:

rs1600414549

Molecular consequence:

NM_007254.4:c.1448+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Developmental and epileptic encephalopathy, 12 (DEE12)
Synonyms:: Early infantile epileptic encephalopathy 12
Identifiers:: MONDO: MONDO:0013389; MedGen: C3150988; OMIM: 613722

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002234141	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 9, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 30039206, 17576681, 9536098, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002234141

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 9, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25.

Leal A, Bogantes-Ledezma S, Ekici AB, Uebe S, Thiel CT, Sticht H, Berghoff M, Berghoff C, Morera B, Meisterernst M, Reis A.

Neurogenetics. 2018 Dec;19(4):215-225. doi: 10.1007/s10048-018-0555-7. Epub 2018 Jul 24.

PubMed [citation]

PMID:: 30039206
PMCID:: PMC6280876

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]

PMID:: 17576681
PMCID:: PMC1934990

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002234141.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This variant disrupts a region of the PNKP protein in which other variant(s) (p.Gln517*) have been determined to be pathogenic (PMID: 30039206). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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. This variant has not been reported in the literature in individuals affected with PNKP-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 16 of the PNKP gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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