19-49861835-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_007254.4(PNKP):​c.1235C>A​(p.Ala412Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000694 in 1,440,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PNKP
NM_007254.4 missense

Scores

3
8
8

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.99
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 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.883

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PNKPNM_007254.4 linkc.1235C>A p.Ala412Asp missense_variant Exon 14 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.1235C>A p.Ala412Asp missense_variant Exon 14 of 17 1 NM_007254.4 ENSP00000323511.2 Q96T60-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.94e-7
AC:
1
AN:
1440406
Hom.:
0
Cov.:
38
AF XY:
0.00000140
AC XY:
1
AN XY:
715696
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:
9.05e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.57
BayesDel_addAF
Uncertain
0.084
D
BayesDel_noAF
Benign
-0.12
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.38
T;T;T;T
Eigen
Uncertain
0.33
Eigen_PC
Benign
0.11
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Benign
0.81
.;T;T;T
M_CAP
Uncertain
0.13
D
MetaRNN
Pathogenic
0.88
D;D;D;D
MetaSVM
Benign
-0.53
T
MutationAssessor
Pathogenic
3.0
M;.;M;.
PrimateAI
Uncertain
0.52
T
PROVEAN
Uncertain
-3.6
D;.;.;.
REVEL
Benign
0.28
Sift
Uncertain
0.029
D;.;.;.
Sift4G
Benign
0.15
T;T;T;T
Polyphen
0.93
P;.;P;.
Vest4
0.76
MutPred
0.64
Loss of loop (P = 0.0203);.;Loss of loop (P = 0.0203);.;
MVP
0.77
MPC
0.57
ClinPred
0.97
D
GERP RS
2.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.53
gMVP
0.89

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-50365092; API