chr19-49867147-G-C

Position:

• chr19-49867147-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_007254.4(PNKP):​c.58C>G​(p.Pro20Ala) 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 benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P20S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: PNKP NM_007254.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.37

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]

PNKP (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-49867147-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.20321071).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNKP	NM_007254.4	c.58C>G	p.Pro20Ala	missense_variant	2/17	ENST00000322344.8	NP_009185.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNKP	ENST00000322344.8	c.58C>G	p.Pro20Ala	missense_variant	2/17	1	NM_007254.4	ENSP00000323511.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	17
DANN	Benign	0.69
DEOGEN2	Benign	0.027	T;T;T;T;T;.;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.90	D;.;D;D;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.20	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	.;L;.;L;.;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.6	.;N;.;.;.;.;.
REVEL	Benign	0.023
Sift	Benign	0.17	.;T;.;.;.;.;.
Sift4G	Benign	0.31	T;T;T;T;T;.;.
Polyphen		0.0070	.;B;.;B;.;.;.
Vest4		0.35
MutPred		0.24		Loss of glycosylation at P20 (P = 0.02);Loss of glycosylation at P20 (P = 0.02);Loss of glycosylation at P20 (P = 0.02);Loss of glycosylation at P20 (P = 0.02);Loss of glycosylation at P20 (P = 0.02);Loss of glycosylation at P20 (P = 0.02);Loss of glycosylation at P20 (P = 0.02);
MVP		0.87
MPC		0.086
ClinPred		0.22	T
GERP RS		4.5
Varity_R		0.16
gMVP		0.17

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: rs3739168; hg19: chr19-50370404;