rs145886749

Positions:

chr19-49861500-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_007254.4(PNKP):c.1397T>C(p.Met466Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,610,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000060 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

PNKP
NM_007254.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 2.11

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23256275).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNKP	NM_007254.4 linkuse as main transcript	c.1397T>C	p.Met466Thr	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.1397T>C	p.Met466Thr	missense_variant	16/17	1	NM_007254.4	P1	Q96T60-1

Frequencies

GnomAD3 genomes

AF:

0.0000603

AC:

AN:

149308

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000290

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000637

AC:

AN:

251108

Hom.:

AF XY:

0.0000737

AC XY:

AN XY:

135730

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.000141

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000145

AC:

212

AN:

1460858

Hom.:

Cov.:

AF XY:

0.000153

AC XY:

111

AN XY:

726740

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000176

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.0000603

AC:

AN:

149308

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

72696

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000290

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000121

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 09, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 05, 2023	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; Has not been previously published as pathogenic or benign to our knowledge -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 16, 2021

The c.1397T>C (p.M466T) alteration is located in exon 16 (coding exon 15) of the PNKP gene. This alteration results from a T to C substitution at nucleotide position 1397, causing the methionine (M) at amino acid position 466 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Developmental and epileptic encephalopathy, 12

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 19, 2022

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 466 of the PNKP protein (p.Met466Thr). This variant is present in population databases (rs145886749, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PNKP-related conditions. ClinVar contains an entry for this variant (Variation ID: 426407). 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 not expected to disrupt PNKP protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.32

T;T;T;T;T

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.85

.;T;T;T;T

M_CAP

Benign

0.075

MetaRNN

Benign

0.23

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.5

D;.;.;.;.

REVEL

Benign

0.13

Sift

Uncertain

0.0020

D;.;.;.;.

Sift4G

Uncertain

0.0040

D;D;D;T;D

Polyphen

0.55

P;.;P;.;.

Vest4

0.53

MVP

0.59

MPC

0.41

ClinPred

0.54

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.43

gMVP

0.63

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

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