19-49861227-T-G

Position:

• chr19-49861227-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007254.4(PNKP):​c.*21A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00721 in 1,489,272 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0075 (70 hom.)
• Consequence: PNKP NM_007254.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.03

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=-0.64).
• BP6: Variant 19-49861227-T-G is Benign according to our data. Variant chr19-49861227-T-G is described in ClinVar as [Benign]. Clinvar id is 329890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00481 (733/152288) while in subpopulation SAS AF= 0.0155 (75/4830). AF 95% confidence interval is 0.0127. There are 1 homozygotes in gnomad4. There are 369 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 70 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNKP	NM_007254.4	c.*21A>C		3_prime_UTR_variant	17/17	ENST00000322344.8	NP_009185.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNKP	ENST00000322344.8	c.*21A>C		3_prime_UTR_variant	17/17	1	NM_007254.4	ENSP00000323511	P1

Frequencies

GnomAD3 genomes AF: 0.00481 AC: 732 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0153

Gnomad FIN AF: 0.00415

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00690

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00661 AC: 1643 AN: 248644 Hom.: 12 AF XY: 0.00763 AC XY: 1031 AN XY: 135064

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00321

Gnomad ASJ exome AF: 0.00340

Gnomad EAS exome AF: 0.000382

Gnomad SAS exome AF: 0.0187

Gnomad FIN exome AF: 0.00551

Gnomad NFE exome AF: 0.00661

Gnomad OTH exome AF: 0.00607

GnomAD4 exome AF: 0.00748 AC: 10001 AN: 1336984 Hom.: 70 Cov.: 20 AF XY: 0.00785 AC XY: 5270 AN XY: 671666

Gnomad4 AFR exome AF: 0.00142

Gnomad4 AMR exome AF: 0.00334

Gnomad4 ASJ exome AF: 0.00322

Gnomad4 EAS exome AF: 0.000128

Gnomad4 SAS exome AF: 0.0186

Gnomad4 FIN exome AF: 0.00520

Gnomad4 NFE exome AF: 0.00749

Gnomad4 OTH exome AF: 0.00676

GnomAD4 genome AF: 0.00481 AC: 733 AN: 152288 Hom.: 1 Cov.: 32 AF XY: 0.00495 AC XY: 369 AN XY: 74472

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0155

Gnomad4 FIN AF: 0.00415

Gnomad4 NFE AF: 0.00690

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00302 Hom.: 0

Bravo AF: 0.00457

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.012
DANN	Benign	0.78

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: rs201872477; hg19: chr19-50364484;