rs372148913

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3_ModeratePP5

The NM_007254.4(PNKP):c.968C>T(p.Thr323Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000827 in 1,583,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T323S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000087 ( 0 hom. )

Consequence

PNKP
NM_007254.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:3

Conservation

PhyloP100: 4.34

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

ataxia - oculomotor apraxia type 4
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P, Laboratory for Molecular Medicine
microcephaly, seizures, and developmental delay
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Charcot-Marie-Tooth disease type 2B2
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PNKP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.878

PP5

Variant 19-49862432-G-A is Pathogenic according to our data. Variant chr19-49862432-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 159803.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNKP	NM_007254.4 link	c.968C>T	p.Thr323Met	missense_variant	Exon 11 of 17	ENST00000322344.8	NP_009185.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNKP	ENST00000322344.8 link	c.968C>T	p.Thr323Met	missense_variant	Exon 11 of 17	1	NM_007254.4	ENSP00000323511.2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000500

AC:

AN:

200044

AF XY:

0.0000464

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000342

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000922

Gnomad OTH exome

AF:

0.000194

GnomAD4 exome

AF:

0.0000874

AC:

125

AN:

1430980

Hom.:

Cov.:

AF XY:

0.0000776

AC XY:

AN XY:

708942

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32884

American (AMR)

AF:

0.0000500

AC:

AN:

40000

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25538

East Asian (EAS)

AF:

0.00

AC:

AN:

38214

South Asian (SAS)

AF:

0.0000122

AC:

AN:

82108

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50806

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.000109

AC:

119

AN:

1096556

Other (OTH)

AF:

0.0000507

AC:

AN:

59166

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000991

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.0000416

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:2

Jan 23, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed multiple times with a second PNKP variant in unrelated patients with features of a PNKP-related disorder referred for genetic testing at GeneDx and in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (PMID: 35354845, 37916443, 32980744); Published functional studies demonstrate a damaging effect and show that this variant causes a significant loss of both 5'-kinase and 3'-phosphatase activity, increases radiation sensitivity, and impairs double strand DNA repair in vitro (PMID: 35354845); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22508754, 35354845, 37916443, 29655203, 34697416, 34040816, 32980744) -

Mar 25, 2021

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 17, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Oct 03, 2024

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.T323M variant (also known as c.968C>T), located in coding exon 10 of the PNKP gene, results from a C to T substitution at nucleotide position 968. The threonine at codon 323 is replaced by methionine, an amino acid with similar properties. This variant has been identified homozygous and in conjunction with other PNKP variants in individuals with seizures, microcephaly, global developmental delay, dyskinesia, abnormal MRI, lissencephaly, and/or polymicrogyria, and other clinical features consistent with PNKP-related neurodevelopmental disorder; in at least one instance, the variants were identified in trans (Lindy AS et al. Epilepsia, 2018 May;59:1062-1071; Garrelfs MR et al. Pediatr Neurol, 2020 Dec;113:26-3; Marcilla Vázquez C et al. J Pediatr Genet, 2021 Jun;10:164-172; Jiang B et al. Sci Rep, 2022 Mar;12:5386; Thuresson AC et al. Mol Genet Genomic Med, 2024 Jan;12:e2295; External communication, 2024). In multiple assays testing PNKP function, this variant showed functionally abnormal results (Jiang B et al. Sci Rep, 2022 Mar;12:5386). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Microcephaly, seizures, and developmental delay

Pathogenic:1

Aug 05, 2013

Genetic Services Laboratory, University of Chicago

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ataxia - oculomotor apraxia type 4

Pathogenic:1

Hadassah Hebrew University Medical Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy, 12

Pathogenic:1

Jun 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 323 of the PNKP protein (p.Thr323Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of PNKP-related conditions (PMID: 29655203, 32980744, 34040816, 35354845; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 159803). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PNKP protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PNKP function (PMID: 35354845). For these reasons, this variant has been classified as Pathogenic. -

PNKP-related disorder

Uncertain:1

Feb 03, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PNKP c.968C>T variant is predicted to result in the amino acid substitution p.Thr323Met. This variant has been reported in the homozygous state, in combination with an additional variant (phase not provided), or with no zygosity provided, in individuals with microcephaly, seizures, and developmental delay (Marcilla Vázquez C et al 2020. PubMed ID: 34040816; Jiang B et al 2022. PubMed ID: 35354845; Lindy et al 2018. PubMed ID: 29655203 Supplemental Table 4; Garrelfs et al. 2020. PubMed ID: 32980744). In vitro studies using an overexpression system suggested that this variant may reduce protein function by multiple mechanisms (Jiang B et al 2022. PubMed ID: 35354845). This variant is reported in 0.0092% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.49

T;D;T;D

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.81

LIST_S2

Pathogenic

0.99

D;.;D;D

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.88

D;D;D;D

MetaSVM

Uncertain

0.37

MutationAssessor

Pathogenic

4.0

.;H;.;H

PhyloP100

4.3

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-5.4

.;D;.;.

REVEL

Uncertain

0.54

Sift

Uncertain

0.0010

.;D;.;.

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

.;D;.;D

Vest4

0.69

MVP

0.85

MPC

0.49

ClinPred

0.99

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.82

gMVP

0.87

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over