rs145307985

chr19-49863722-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_007254.4(PNKP):c.783G>A(p.Pro261=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00511 in 1,558,080 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0053 (24 hom.)
• Consequence: PNKP NM_007254.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -3.90

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 19-49863722-C-T is Benign according to our data. Variant chr19-49863722-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 138712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49863722-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.9 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00351 (535/152284) while in subpopulation NFE AF= 0.00594 (404/68010). AF 95% confidence interval is 0.00546. There are 2 homozygotes in gnomad4. There are 226 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNKP	NM_007254.4	c.783G>A	p.Pro261=	synonymous_variant	8/17	ENST00000322344.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNKP	ENST00000322344.8	c.783G>A	p.Pro261=	synonymous_variant	8/17	1	NM_007254.4	P1

Frequencies

GnomAD3 genomes AF: 0.00352 AC: 535 AN: 152166 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00451

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00594

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00280 AC: 459 AN: 164102 Hom.: 3 AF XY: 0.00272 AC XY: 237 AN XY: 87280

Gnomad AFR exome AF: 0.000954

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.000933

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000128

Gnomad FIN exome AF: 0.000577

Gnomad NFE exome AF: 0.00544

Gnomad OTH exome AF: 0.00510

GnomAD4 exome AF: 0.00528 AC: 7425 AN: 1405796 Hom.: 24 Cov.: 31 AF XY: 0.00509 AC XY: 3533 AN XY: 694180

Gnomad4 AFR exome AF: 0.000809

Gnomad4 AMR exome AF: 0.00278

Gnomad4 ASJ exome AF: 0.000753

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000388

Gnomad4 FIN exome AF: 0.000713

Gnomad4 NFE exome AF: 0.00643

Gnomad4 OTH exome AF: 0.00424

GnomAD4 genome AF: 0.00351 AC: 535 AN: 152284 Hom.: 2 Cov.: 33 AF XY: 0.00304 AC XY: 226 AN XY: 74460

Gnomad4 AFR AF: 0.00115

Gnomad4 AMR AF: 0.00451

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00594

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00452 Hom.: 1

Bravo AF: 0.00389

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 23, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 21, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Microcephaly, seizures, and developmental delay Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jun 05, 2017	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 14, 2016

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2024

PNKP: BP4, BP7, BS2 -

Developmental and epileptic encephalopathy, 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Benign	1.1
Dann	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs145307985; hg19: chr19-50366979;