rs3739200

Positions:

• chr19-49862520-A-AG

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_007254.4(PNKP):​c.936+17_936+18insC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 1,605,176 control chromosomes in the GnomAD database, including 169 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.011 (23 hom., cov: 32)
  • Exomes 𝑓: 0.012 (146 hom.)
• Consequence: PNKP NM_007254.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.889

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 -9 ACMG points.

• BP6: Variant 19-49862520-A-AG is Benign according to our data. Variant chr19-49862520-A-AG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 206371.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0106 (1608/152224) while in subpopulation AMR AF= 0.0286 (438/15300). AF 95% confidence interval is 0.0264. There are 23 homozygotes in gnomad4. There are 759 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNKP	NM_007254.4	c.936+17_936+18insC		intron_variant		ENST00000322344.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNKP	ENST00000322344.8	c.936+17_936+18insC		intron_variant		1	NM_007254.4	P1

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1612 AN: 152106 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0287

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.0201

GnomAD3 exomes AF: 0.0109 AC: 2507 AN: 229218 Hom.: 21 AF XY: 0.0113 AC XY: 1414 AN XY: 124942

Gnomad AFR exome AF: 0.00219

Gnomad AMR exome AF: 0.0176

Gnomad ASJ exome AF: 0.0307

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00586

Gnomad FIN exome AF: 0.00129

Gnomad NFE exome AF: 0.0127

Gnomad OTH exome AF: 0.0206

GnomAD4 exome AF: 0.0123 AC: 17873 AN: 1452952 Hom.: 146 Cov.: 35 AF XY: 0.0124 AC XY: 8938 AN XY: 722230

Gnomad4 AFR exome AF: 0.00270

Gnomad4 AMR exome AF: 0.0180

Gnomad4 ASJ exome AF: 0.0311

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00601

Gnomad4 FIN exome AF: 0.00160

Gnomad4 NFE exome AF: 0.0131

Gnomad4 OTH exome AF: 0.0139

GnomAD4 genome AF: 0.0106 AC: 1608 AN: 152224 Hom.: 23 Cov.: 32 AF XY: 0.0102 AC XY: 759 AN XY: 74412

Gnomad4 AFR AF: 0.00233

Gnomad4 AMR AF: 0.0286

Gnomad4 ASJ AF: 0.0268

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00642

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.0132

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.0137 Hom.: 3

Bravo AF: 0.0116

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, flagged submission	clinical testing	GeneDx	Mar 19, 2015	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:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Developmental and epileptic encephalopathy, 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

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: rs3739200; hg19: chr19-50365777;