rs145904995

chr19-49864236-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_007254.4(PNKP):c.579G>A(p.Arg193=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00297 in 1,614,146 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (56 hom.)
• Consequence: PNKP NM_007254.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 3.53

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 Benign. Variant got -15 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 19-49864236-C-T is Benign according to our data. Variant chr19-49864236-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 95484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49864236-C-T is described in Lovd as [Likely_benign]. Variant chr19-49864236-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00246 (374/152314) while in subpopulation SAS AF= 0.0141 (68/4824). AF 95% confidence interval is 0.0114. There are 5 homozygotes in gnomad4. There are 193 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNKP	NM_007254.4	c.579G>A	p.Arg193=	splice_region_variant, synonymous_variant	6/17	ENST00000322344.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNKP	ENST00000322344.8	c.579G>A	p.Arg193=	splice_region_variant, synonymous_variant	6/17	1	NM_007254.4	P1

Frequencies

GnomAD3 genomes AF: 0.00247 AC: 376 AN: 152196 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.0418

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0145

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00165

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00438 AC: 1101 AN: 251440 Hom.: 14 AF XY: 0.00504 AC XY: 685 AN XY: 135896

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.0430

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0110

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00201

Gnomad OTH exome AF: 0.00749

GnomAD4 exome AF: 0.00303 AC: 4423 AN: 1461832 Hom.: 56 Cov.: 33 AF XY: 0.00339 AC XY: 2464 AN XY: 727220

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00159

Gnomad4 ASJ exome AF: 0.0434

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0118

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.00156

Gnomad4 OTH exome AF: 0.00555

GnomAD4 genome AF: 0.00246 AC: 374 AN: 152314 Hom.: 5 Cov.: 33 AF XY: 0.00259 AC XY: 193 AN XY: 74474

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.0418

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0141

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00165

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00385 Hom.: 5

Bravo AF: 0.00232

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.00289

EpiControl AF: 0.00332

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 05, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 15, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	PNKP: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 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. -

Microcephaly, seizures, and developmental delay Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 24, 2021

- -

Developmental and epileptic encephalopathy, 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.14
Cadd	Benign	20
Dann	Benign	0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.34		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs145904995; hg19: chr19-50367493; COSMIC: COSV55587900; COSMIC: COSV55587900;