chr19-49861253-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_007254.4(PNKP):​c.1561G>A​(p.Gly521Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000816 in 1,593,850 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 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

PNKP
NM_007254.4 missense

Scores

2
8
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.92
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 Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.31683892).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PNKPNM_007254.4 linkuse as main transcriptc.1561G>A p.Gly521Ser missense_variant 17/17 ENST00000322344.8 NP_009185.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PNKPENST00000322344.8 linkuse as main transcriptc.1561G>A p.Gly521Ser missense_variant 17/171 NM_007254.4 ENSP00000323511 P1Q96T60-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152154
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
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:
0.00000399
AC:
1
AN:
250348
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135628
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:
0.00000885
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000763
AC:
11
AN:
1441696
Hom.:
0
Cov.:
29
AF XY:
0.00000696
AC XY:
5
AN XY:
718644
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:
0.0000101
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152154
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74334
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.0000312
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 12 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 16, 2022This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 521 of the PNKP protein (p.Gly521Ser). This variant has not been reported in the literature in individuals affected with PNKP-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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
Benign
0.24
BayesDel_addAF
Benign
-0.014
T
BayesDel_noAF
Benign
-0.26
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.15
T;T;T;T
Eigen
Uncertain
0.44
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.94
.;D;D;D
M_CAP
Uncertain
0.27
D
MetaRNN
Benign
0.32
T;T;T;T
MetaSVM
Benign
-0.76
T
MutationAssessor
Uncertain
2.4
M;.;M;.
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
-0.64
N;.;.;.
REVEL
Benign
0.17
Sift
Pathogenic
0.0
D;.;.;.
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
1.0
D;.;D;.
Vest4
0.43
MutPred
0.25
Gain of phosphorylation at G521 (P = 0.1215);.;Gain of phosphorylation at G521 (P = 0.1215);.;
MVP
0.63
MPC
0.48
ClinPred
0.88
D
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.51
gMVP
0.60

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: rs1289682803; hg19: chr19-50364510; API