chr19-49867147-G-T

Position:

• chr19-49867147-G-T

Variant summary

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

The ENST00000322344.8(PNKP):​c.58C>A​(p.Pro20Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,459,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. P20S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PNKP ENST00000322344.8 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• 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]

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=0.23938936).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNKP	NM_007254.4	c.58C>A	p.Pro20Thr	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>A	p.Pro20Thr	missense_variant	2/17	1	NM_007254.4	ENSP00000323511	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000206 AC: 5 AN: 242362 Hom.: 0 AF XY: 0.0000150 AC XY: 2 AN XY: 133128

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1459972 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726342

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.0000113

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 11, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22508754) -

Charcot-Marie-Tooth disease type 2B2;C3150667:Microcephaly, seizures, and developmental delay;C4225397:Ataxia - oculomotor apraxia type 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 01, 2022

- -

Developmental and epileptic encephalopathy, 12 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 29, 2022

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 tolerated. ClinVar contains an entry for this variant (Variation ID: 471506). This variant has not been reported in the literature in individuals affected with PNKP-related conditions. This variant is present in population databases (rs3739168, gnomAD 0.01%). This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 20 of the PNKP protein (p.Pro20Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.028	T;T;T;T;T;.;T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.91	D;.;D;D;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.24	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	.;M;.;M;.;.;.
MutationTaster	Benign	0.71	N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.6	.;N;.;.;.;.;.
REVEL	Benign	0.066
Sift	Benign	0.030	.;D;.;.;.;.;.
Sift4G	Benign	0.071	T;T;T;T;T;.;.
Polyphen		0.64	.;P;.;P;.;.;.
Vest4		0.46
MutPred		0.23		Gain of phosphorylation at P20 (P = 0.0103);Gain of phosphorylation at P20 (P = 0.0103);Gain of phosphorylation at P20 (P = 0.0103);Gain of phosphorylation at P20 (P = 0.0103);Gain of phosphorylation at P20 (P = 0.0103);Gain of phosphorylation at P20 (P = 0.0103);Gain of phosphorylation at P20 (P = 0.0103);
MVP		0.87
MPC		0.12
ClinPred		0.50	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.29

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;