NM_007254.4:c.1009G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_007254.4(PNKP):​c.1009G>C​(p.Glu337Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,554,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E337E) has been classified as Likely benign.

Frequency

Genomes: š‘“ 0.000059 ( 0 hom., cov: 32)
Exomes š‘“: 0.000012 ( 0 hom. )

Consequence

PNKP
NM_007254.4 missense

Scores

2
17

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 0.268
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.024107128).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PNKPNM_007254.4 linkc.1009G>C p.Glu337Gln missense_variant Exon 11 of 17 ENST00000322344.8 NP_009185.2 Q96T60-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PNKPENST00000322344.8 linkc.1009G>C p.Glu337Gln missense_variant Exon 11 of 17 1 NM_007254.4 ENSP00000323511.2 Q96T60-1

Frequencies

GnomAD3 genomes
AF:
0.0000593
AC:
9
AN:
151874
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00877
Gnomad AMR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000249
AC:
4
AN:
160814
Hom.:
0
AF XY:
0.0000233
AC XY:
2
AN XY:
85802
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000394
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000835
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000318
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000121
AC:
17
AN:
1402710
Hom.:
0
Cov.:
37
AF XY:
0.0000116
AC XY:
8
AN XY:
692370
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000276
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000829
Gnomad4 SAS exome
AF:
0.0000126
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000370
Gnomad4 OTH exome
AF:
0.000138
GnomAD4 genome
AF:
0.0000593
AC:
9
AN:
151874
Hom.:
0
Cov.:
32
AF XY:
0.0000809
AC XY:
6
AN XY:
74180
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.0000907
ExAC
AF:
0.0000176
AC:
2
Asia WGS
AF:
0.00173
AC:
6
AN:
3474

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Jan 08, 2020
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.E337Q variant (also known as c.1009G>C), located in coding exon 10 of the PNKP gene, results from a G to C substitution at nucleotide position 1009. The glutamic acid at codon 337 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in a subject with juvenile myoclonic epilepsy (Lee CG et al. PLoS ONE, 2018 Jun;13:e0199321). This amino acid position is not well conserved in available vertebrate species, and glutamine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Charcot-Marie-Tooth disease type 2B2;C3150667:Microcephaly, seizures, and developmental delay;C4225397:Ataxia - oculomotor apraxia type 4 Uncertain:1
May 01, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 12 Uncertain:1
Aug 20, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 337 of the PNKP protein (p.Glu337Gln). This variant is present in population databases (rs780121125, gnomAD 0.008%). This missense change has been observed in individual(s) with juvenile myoclonic epilepsy (PMID: 29924869). ClinVar contains an entry for this variant (Variation ID: 391407). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. -

not provided Benign:1
Apr 03, 2019
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.070
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.47
CADD
Benign
10
DANN
Benign
0.74
DEOGEN2
Benign
0.024
T;T;T;T
Eigen
Benign
-0.78
Eigen_PC
Benign
-0.87
FATHMM_MKL
Benign
0.17
N
LIST_S2
Benign
0.72
T;.;T;T
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.024
T;T;T;T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
1.3
.;L;.;L
PrimateAI
Uncertain
0.63
T
PROVEAN
Benign
-0.61
.;N;.;.
REVEL
Benign
0.080
Sift
Benign
0.36
.;T;.;.
Sift4G
Benign
0.38
T;T;T;T
Polyphen
0.55
.;P;.;P
Vest4
0.20
MVP
0.59
MPC
0.088
ClinPred
0.053
T
GERP RS
-1.1
Varity_R
0.029
gMVP
0.49

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

LitVar

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

Other links and lift over

dbSNP: rs780121125; hg19: chr19-50365648; API