rs2257103

Positions:

• chr19-49866809-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007254.4(PNKP):​c.151+245G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 600,164 control chromosomes in the GnomAD database, including 47,556 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (12038 hom., cov: 33)
  • Exomes 𝑓: 0.39 (35518 hom.)
• Consequence: PNKP NM_007254.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.99

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.2666664E-4).
• BP6: Variant 19-49866809-C-T is Benign according to our data. Variant chr19-49866809-C-T is described in ClinVar as [Benign]. Clinvar id is 667942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.472 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNKP	NM_007254.4	c.151+245G>A		intron_variant		ENST00000322344.8	NP_009185.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNKP	ENST00000322344.8	c.151+245G>A		intron_variant		1	NM_007254.4	ENSP00000323511	P1

Frequencies

GnomAD3 genomes AF: 0.395 AC: 60094 AN: 152002 Hom.: 12041 Cov.: 33

Gnomad AFR AF: 0.429

Gnomad AMI AF: 0.503

Gnomad AMR AF: 0.325

Gnomad ASJ AF: 0.445

Gnomad EAS AF: 0.209

Gnomad SAS AF: 0.489

Gnomad FIN AF: 0.389

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.395

Gnomad OTH AF: 0.402

GnomAD4 exome AF: 0.392 AC: 175494 AN: 448044 Hom.: 35518 Cov.: 4 AF XY: 0.399 AC XY: 94177 AN XY: 236074

Gnomad4 AFR exome AF: 0.422

Gnomad4 AMR exome AF: 0.303

Gnomad4 ASJ exome AF: 0.462

Gnomad4 EAS exome AF: 0.209

Gnomad4 SAS exome AF: 0.491

Gnomad4 FIN exome AF: 0.375

Gnomad4 NFE exome AF: 0.398

Gnomad4 OTH exome AF: 0.392

GnomAD4 genome AF: 0.395 AC: 60105 AN: 152120 Hom.: 12038 Cov.: 33 AF XY: 0.396 AC XY: 29466 AN XY: 74372

Gnomad4 AFR AF: 0.428

Gnomad4 AMR AF: 0.325

Gnomad4 ASJ AF: 0.445

Gnomad4 EAS AF: 0.208

Gnomad4 SAS AF: 0.488

Gnomad4 FIN AF: 0.389

Gnomad4 NFE AF: 0.395

Gnomad4 OTH AF: 0.399

Alfa AF: 0.395 Hom.: 2552

Bravo AF: 0.390

TwinsUK AF: 0.406 AC: 1506

ALSPAC AF: 0.395 AC: 1524

Asia WGS AF: 0.318 AC: 1108 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	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 specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jul 15, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 41% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 38. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.88
DANN	Benign	0.85
DEOGEN2	Benign	0.0074	T
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.00053	T
MutationTaster	Benign	1.0	P
GERP RS		-5.3

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: rs2257103; hg19: chr19-50370066;