19-49864383-G-C

Variant names:

• chr19-49864383-G-C
• rs144284975
• NM_007254.4:c.519C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_007254.4(PNKP):​c.519C>G​(p.Asp173Glu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PNKP NM_007254.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.53

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 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, 0.909

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNKP	NM_007254.4	c.519C>G	p.Asp173Glu	missense_variant	Exon 5 of 17	ENST00000322344.8	NP_009185.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNKP	ENST00000322344.8	c.519C>G	p.Asp173Glu	missense_variant	Exon 5 of 17	1	NM_007254.4	ENSP00000323511.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	8.8
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;D;T;D;T;.;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.96	D;.;D;D;D;D;T
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	4.1	.;H;.;H;.;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.0	.;D;.;.;.;.;.
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	.;D;.;.;.;.;.
Sift4G	Uncertain	0.0030	D;D;D;D;D;.;.
Polyphen		1.0	.;D;.;D;.;.;.
Vest4		0.78
MutPred		0.80		Gain of glycosylation at T178 (P = 0.2502);Gain of glycosylation at T178 (P = 0.2502);Gain of glycosylation at T178 (P = 0.2502);Gain of glycosylation at T178 (P = 0.2502);Gain of glycosylation at T178 (P = 0.2502);Gain of glycosylation at T178 (P = 0.2502);Gain of glycosylation at T178 (P = 0.2502);
MVP		0.86
MPC		0.47
ClinPred		1.0	D
GERP RS		-9.0
Varity_R		0.93
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs144284975; hg19: chr19-50367640;