rs201221600

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_007254.4(PNKP):c.19C>T(p.Pro7Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,611,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. P7L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

PNKP
NM_007254.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 0.297

Publications

5 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0426279).

BP6

Variant 19-49867186-G-A is Benign according to our data. Variant chr19-49867186-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 206421. Variant chr19-49867186-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 206421. Variant chr19-49867186-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 206421. Variant chr19-49867186-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 206421. Variant chr19-49867186-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 206421. Variant chr19-49867186-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 206421. Variant chr19-49867186-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 206421. Variant chr19-49867186-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 206421. Variant chr19-49867186-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 206421. Variant chr19-49867186-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 206421. Variant chr19-49867186-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 206421. Variant chr19-49867186-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 206421. Variant chr19-49867186-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 206421. Variant chr19-49867186-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 206421. Variant chr19-49867186-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 206421. Variant chr19-49867186-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 206421. Variant chr19-49867186-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 206421. Variant chr19-49867186-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 206421. Variant chr19-49867186-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 206421. Variant chr19-49867186-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 206421. Variant chr19-49867186-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 206421. Variant chr19-49867186-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 206421. Variant chr19-49867186-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 206421. Variant chr19-49867186-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 206421.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNKP	NM_007254.4 link	c.19C>T	p.Pro7Ser	missense_variant	Exon 2 of 17	ENST00000322344.8	NP_009185.2	Q96T60-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNKP	ENST00000322344.8 link	c.19C>T	p.Pro7Ser	missense_variant	Exon 2 of 17	1	NM_007254.4	ENSP00000323511.2		Q96T60-1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000176

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000833

AC:

AN:

240116

AF XY:

0.0000909

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000474

Gnomad NFE exome

AF:

0.000159

Gnomad OTH exome

AF:

0.000171

GnomAD4 exome

AF:

0.000179

AC:

261

AN:

1459304

Hom.:

Cov.:

AF XY:

0.000169

AC XY:

123

AN XY:

725902

show subpopulations

African (AFR)

AF:

0.0000897

AC:

AN:

33448

American (AMR)

AF:

0.0000448

AC:

AN:

44614

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26084

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.00

AC:

AN:

86188

European-Finnish (FIN)

AF:

0.0000767

AC:

AN:

52158

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5624

European-Non Finnish (NFE)

AF:

0.000216

AC:

240

AN:

1111252

Other (OTH)

AF:

0.000199

AC:

AN:

60272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

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:

0.000125

AC:

AN:

152352

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41592

American (AMR)

AF:

0.000131

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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:

0.000226

Hom.:

Bravo

AF:

0.000136

ExAC

AF:

0.0000666

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Apr 17, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22508754) -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PNKP: BP4 -

not specified

Uncertain:1

Dec 05, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Microcephaly, seizures, and developmental delay

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Developmental and epileptic encephalopathy, 12

Uncertain:1

Oct 28, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 7 of the PNKP protein (p.Pro7Ser). This variant is present in population databases (rs201221600, 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: 206421). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Inborn genetic diseases

Benign:1

Jan 15, 2025

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.0058

T;T;T;T;T;.;T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.090

LIST_S2

Benign

0.85

D;.;D;D;D;D;D;.

M_CAP

Benign

0.010

MetaRNN

Benign

0.043

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;N;.;N;.;.;.;.

PhyloP100

0.30

PrimateAI

Benign

0.36

PROVEAN

Benign

0.53

.;N;.;.;.;.;.;.

REVEL

Benign

0.064

Sift

Benign

0.16

.;T;.;.;.;.;.;.

Sift4G

Benign

0.17

T;T;T;T;T;.;.;.

Polyphen

0.049

.;B;.;B;.;.;.;.

Vest4

0.25

MVP

0.33

MPC

0.091

ClinPred

0.027

GERP RS

0.72

PromoterAI

0.088

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.042

gMVP

0.10

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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