rs267606957

Positions:

• chr19-49864376-G-A
• chr19-49864376-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The ENST00000322344.8(PNKP):​c.526C>T​(p.Leu176Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L176P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PNKP ENST00000322344.8 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.25

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant 19-49864376-G-A is Pathogenic according to our data. Variant chr19-49864376-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4848.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-49864376-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNKP	NM_007254.4	c.526C>T	p.Leu176Phe	missense_variant	5/17	ENST00000322344.8	NP_009185.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNKP	ENST00000322344.8	c.526C>T	p.Leu176Phe	missense_variant	5/17	1	NM_007254.4	ENSP00000323511	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Microcephaly, seizures, and developmental delay Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.47	T;D;T;D;T;.;T
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D;.;D;D;D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	3.5	.;M;.;M;.;.;.
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.2	.;D;.;.;.;.;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0080	.;D;.;.;.;.;.
Sift4G	Uncertain	0.0070	D;D;D;D;D;.;.
Polyphen		1.0	.;D;.;D;.;.;.
Vest4		0.74
MutPred		0.90		Gain of phosphorylation at T179 (P = 0.1768);Gain of phosphorylation at T179 (P = 0.1768);Gain of phosphorylation at T179 (P = 0.1768);Gain of phosphorylation at T179 (P = 0.1768);Gain of phosphorylation at T179 (P = 0.1768);Gain of phosphorylation at T179 (P = 0.1768);Gain of phosphorylation at T179 (P = 0.1768);
MVP		0.86
MPC		0.49
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.79
gMVP		0.77

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

Other links and lift over

dbSNP: rs267606957; hg19: chr19-50367633; COSMIC: COSV55586666; COSMIC: COSV55586666;