19-49861166-T-C

Position:

• chr19-49861166-T-C

Variant summary

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

The ENST00000636840.1(PNKP):​c.59+442A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0372 in 970,474 control chromosomes in the GnomAD database, including 1,209 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (94 hom., cov: 32)
  • Exomes 𝑓: 0.039 (1115 hom.)
• Consequence: PNKP ENST00000636840.1 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.47

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 (BayesDel_noAF=-0.85).
• BP6: Variant 19-49861166-T-C is Benign according to our data. Variant chr19-49861166-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1203607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNKP	NM_007254.4			downstream_gene_variant		ENST00000322344.8	NP_009185.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNKP	ENST00000322344.8			downstream_gene_variant		1	NM_007254.4	ENSP00000323511	P1

Frequencies

GnomAD3 genomes AF: 0.0262 AC: 3979 AN: 152118 Hom.: 91 Cov.: 32

Gnomad AFR AF: 0.00676

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.0178

Gnomad ASJ AF: 0.0441

Gnomad EAS AF: 0.0594

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.0192

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0300

Gnomad OTH AF: 0.0278

GnomAD4 exome AF: 0.0392 AC: 32084 AN: 818238 Hom.: 1115 Cov.: 12 AF XY: 0.0431 AC XY: 18560 AN XY: 430832

Gnomad4 AFR exome AF: 0.00736

Gnomad4 AMR exome AF: 0.0120

Gnomad4 ASJ exome AF: 0.0429

Gnomad4 EAS exome AF: 0.0732

Gnomad4 SAS exome AF: 0.118

Gnomad4 FIN exome AF: 0.0236

Gnomad4 NFE exome AF: 0.0311

Gnomad4 OTH exome AF: 0.0362

GnomAD4 genome AF: 0.0262 AC: 3987 AN: 152236 Hom.: 94 Cov.: 32 AF XY: 0.0265 AC XY: 1976 AN XY: 74430

Gnomad4 AFR AF: 0.00674

Gnomad4 AMR AF: 0.0178

Gnomad4 ASJ AF: 0.0441

Gnomad4 EAS AF: 0.0595

Gnomad4 SAS AF: 0.122

Gnomad4 FIN AF: 0.0192

Gnomad4 NFE AF: 0.0300

Gnomad4 OTH AF: 0.0318

Alfa AF: 0.0204 Hom.: 16

Bravo AF: 0.0229

Asia WGS AF: 0.122 AC: 424 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.069
DANN	Benign	0.59

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3739209; hg19: chr19-50364423;