rs779492301

Variant names:

• chr19-49864363-C-G
• NM_007254.4:c.539G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-49864363-C-G
• chr19-49864363-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_007254.4(PNKP):​c.539G>C​(p.Arg180Pro) 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R180S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PNKP NM_007254.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.360

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36983797).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNKP	NM_007254.4	c.539G>C	p.Arg180Pro	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.539G>C	p.Arg180Pro	missense_variant	Exon 5 of 17	1	NM_007254.4	ENSP00000323511.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 12 Uncertain:1

Mar 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with PNKP-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 180 of the PNKP protein (p.Arg180Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.096	T;T;T;T;T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.97	D;.;D;D;D;D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.37	T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.16	.;N;.;N;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.3	.;D;.;.;.;.
REVEL	Benign	0.26
Sift	Uncertain	0.014	.;D;.;.;.;.
Sift4G	Uncertain	0.014	D;D;D;D;D;.
Polyphen		0.95	.;P;.;P;.;.
Vest4		0.50
MutPred		0.61		Loss of catalytic residue at R180 (P = 0.0191);Loss of catalytic residue at R180 (P = 0.0191);Loss of catalytic residue at R180 (P = 0.0191);Loss of catalytic residue at R180 (P = 0.0191);Loss of catalytic residue at R180 (P = 0.0191);Loss of catalytic residue at R180 (P = 0.0191);
MVP		0.75
MPC		0.44
ClinPred		0.94	D
GERP RS		2.7
Varity_R		0.74
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr19-50367620;