rs3739206

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_007254.4(PNKP):c.1433T>G(p.Val478Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,612,998 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V478I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0024 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 82 hom. )

Consequence

PNKP
NM_007254.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.00

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0033710897).

BP6

Variant 19-49861464-A-C is Benign according to our data. Variant chr19-49861464-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 138723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49861464-A-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.058 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNKP	NM_007254.4 linkuse as main transcript	c.1433T>G	p.Val478Gly	missense_variant	16/17	ENST00000322344.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNKP	ENST00000322344.8 linkuse as main transcript	c.1433T>G	p.Val478Gly	missense_variant	16/17	1	NM_007254.4	P1	Q96T60-1

Frequencies

GnomAD3 genomes

AF:

0.00239

AC:

361

AN:

151248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000462

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000658

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0638

Gnomad SAS

AF:

0.00187

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.00240

GnomAD3 exomes

AF:

0.00520

AC:

1307

AN:

251366

Hom.:

AF XY:

0.00467

AC XY:

635

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.0672

Gnomad SAS exome

AF:

0.00118

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00178

AC:

2602

AN:

1461636

Hom.:

Cov.:

AF XY:

0.00171

AC XY:

1242

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.000230

Gnomad4 EAS exome

AF:

0.0528

Gnomad4 SAS exome

AF:

0.00148

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.00553

GnomAD4 genome

AF:

0.00239

AC:

361

AN:

151362

Hom.:

Cov.:

AF XY:

0.00270

AC XY:

200

AN XY:

73960

show subpopulations

Gnomad4 AFR

AF:

0.000461

Gnomad4 AMR

AF:

0.0000657

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0637

Gnomad4 SAS

AF:

0.00188

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000295

Gnomad4 OTH

AF:

0.00285

Alfa

AF:

0.00223

Hom.:

Bravo

AF:

0.00329

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00525

AC:

637

Asia WGS

AF:

0.0270

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 28, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 14, 2015	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 01, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Microcephaly, seizures, and developmental delay

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Developmental and epileptic encephalopathy, 12

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.12

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Benign

0.36

T;T;T;T;T

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.81

MetaRNN

Benign

0.0034

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-6.3

D;.;.;.;.

REVEL

Uncertain

0.32

Sift

Uncertain

0.0010

D;.;.;.;.

Sift4G

Uncertain

0.059

T;T;T;T;D

Polyphen

0.96

D;.;D;.;.

Vest4

0.67

MVP

0.75

MPC

0.41

ClinPred

0.072

GERP RS

4.4

Varity_R

0.70

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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