Variant rs587784365 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_007254.4(PNKP):c.1269_1270insGGGTCGCCATCGACAAC(p.Thr424GlyfsTer49) variant causes a frameshift change. The variant allele was found at a frequency of 0.000297 in 1,574,586 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 0 hom. )

Consequence

PNKP
NM_007254.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:18

Conservation

PhyloP100: 5.04

Variant links:

Genes affected

PNKP (HGNC:9154): (polynucleotide kinase 3'-phosphatase) This locus represents a gene involved in DNA repair. In response to ionizing radiation or oxidative damage, the protein encoded by this locus catalyzes 5' phosphorylation and 3' dephosphorylation of nucleic acids. Mutations at this locus have been associated with microcephaly, seizures, and developmental delay.[provided by RefSeq, Sep 2010]

PNKP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-49861800-T-TGTTGTCGATGGCGACCC is Pathogenic according to our data. Variant chr19-49861800-T-TGTTGTCGATGGCGACCC is described in ClinVar as [Pathogenic]. Clinvar id is 4847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNKP	NM_007254.4 linkuse as main transcript	c.1269_1270insGGGTCGCCATCGACAAC	p.Thr424GlyfsTer49	frameshift_variant	14/17	ENST00000322344.8	NP_009185.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNKP	ENST00000322344.8 linkuse as main transcript	c.1269_1270insGGGTCGCCATCGACAAC	p.Thr424GlyfsTer49	frameshift_variant	14/17	1	NM_007254.4	ENSP00000323511	P1	Q96T60-1

Frequencies

GnomAD3 genomes

AF:

0.000185

AC:

AN:

151534

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000169

AC:

AN:

189632

Hom.:

AF XY:

0.000204

AC XY:

AN XY:

102708

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000285

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000309

AC:

440

AN:

1422936

Hom.:

Cov.:

AF XY:

0.000292

AC XY:

206

AN XY:

705416

show subpopulations

Gnomad4 AFR exome

AF:

0.0000313

Gnomad4 AMR exome

AF:

0.000182

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000212

Gnomad4 NFE exome

AF:

0.000386

Gnomad4 OTH exome

AF:

0.000135

GnomAD4 genome

AF:

0.000185

AC:

AN:

151650

Hom.:

Cov.:

AF XY:

0.000189

AC XY:

AN XY:

74146

show subpopulations

Gnomad4 AFR

AF:

0.0000244

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000383

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000144

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 01, 2022	Published functional studies demonstrate a damaging effect showing that the variant reduces or eliminates PNKP DNA kinase activity (Reynolds et al., 2012); Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 98 amino acids are lost and replaced with 48 incorrect amino acids (HGMD); This variant is associated with the following publications: (PMID: 23224214, 25558065, 23921166, 22508754, 25728773, 20118933, 29498415, 28333917, 30956058, 29655203, 30267214, 30214071, 31707899, 31436889, 34402213, 31589614, 31110700, 32504494) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 13, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	PNKP: PM3:Very Strong, PVS1, PM2, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 20, 2019	- -

Microcephaly, seizures, and developmental delay

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ataxia-oculomotor apraxia 4 (MIM#616267), and microcephaly, seizures, and developmental delay (MIM#613402). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected (PMID: 22508754). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (38 heterozygotes, 0 homozygotes). (SP) 0600 - Variant results in the loss of part of the annotated AAA domain (PDB). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been described as pathogenic in multiple homozygous and compound heterozygous patients, with either ataxia-oculomotor apraxia 4 or microcephaly, seizures and developmental delay (ClinVar, PMID: 31436889, PMID: 31707899). (SP) 1102 - Strong phenotype match for this individual. (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (p.(Ser430Lysfs*39)) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 05, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 05, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Service de Génétique Moléculaire, Hôpital Robert Debré	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jan 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institut de Recherche Interdisciplinaire en Biologie Humaine et Moleculaire, Universite Libre de Bruxelles	Jan 01, 2020	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2019

The c.1253_1269dup17 pathogenic mutation, located in coding exon 13 of the PNKP gene, results from a duplication of GGGTCGCCATCGACAAC at nucleotide position 1253, causing a translational frameshift with a predicted alternate stop codon (p.T424Gfs*49). This frameshift occurs at the 3' terminus of PNKP, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 98 amino acids of the protein. The exact functional impact of these altered amino acids is unknown at this time. However, this variant has been reported in compound heterozygote and homozygous individuals with microcephaly, seizures and developmental delay, as well as ataxia with oculomotor apraxia type 4 (Shen J et al. Nat. Genet., 2010 Mar;42:245-9; Poulton C et al. Neurogenetics, 2013 Feb;14:43-51; Bras J et al. Am. J. Hum. Genet., 2015 Mar;96:474-9; Scholz C et al. Clin. Genet., 2018 Jul;94:185-186). This variant has also been shown to lose DNA kinase activity in functional studies (Reynolds JJ et al. Nucleic Acids Res., 2012 Aug;40:6608-19). Based on our internal structural assessment, this alteration results in loss of large parts of the polynucleotide kinase domain, including helices involved in DNA and NTP binding (Garces F et al. Mol. Cell, 2011 Nov;44:385-96). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Abnormality of the nervous system

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Intellectual disability

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

Apr 20, 2020

- -

Ataxia - oculomotor apraxia type 4

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 05, 2015

- -

Developmental and epileptic encephalopathy, 12

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 02, 2023

This sequence change creates a premature translational stop signal (p.Thr424Glyfs*49) in the PNKP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 98 amino acid(s) of the PNKP protein. This variant is present in population databases (rs587784365, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with microcephaly, early-onset, intractable seizures and developmental delay (MCSZ), ataxia with oculomotor apraxia, and progressive cerebellar atrophy and polyneuropathy (PMID: 20118933, 23224214, 25558065, 25728773). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1250_1251insAACGGGTCGCCATCGAC (p.R418Tfs*55). ClinVar contains an entry for this variant (Variation ID: 4847). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects PNKP function (PMID: 22508754). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over