19-49861166-T-C

Variant names:

• chr19-49861166-T-C
• rs3739209
• ENST00000636840.1:c.57+442A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000636840.1(PNKP):​c.57+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
• Publications: 1 publications found

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]

PNKP Gene-Disease associations (from GenCC):

• ataxia - oculomotor apraxia type 4

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P, Laboratory for Molecular Medicine
• microcephaly, seizures, and developmental delay

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Charcot-Marie-Tooth disease type 2B2

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
PNKP	NM_007254.4	c.*82A>G		downstream_gene_variant		ENST00000322344.8	NP_009185.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNKP	ENST00000322344.8	c.*82A>G		downstream_gene_variant		1	NM_007254.4	ENSP00000323511.2

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

African (AFR) AF: 0.00736 AC: 157 AN: 21342

American (AMR) AF: 0.0120 AC: 524 AN: 43756

Ashkenazi Jewish (ASJ) AF: 0.0429 AC: 942 AN: 21948

East Asian (EAS) AF: 0.0732 AC: 2689 AN: 36722

South Asian (SAS) AF: 0.118 AC: 8584 AN: 72844

European-Finnish (FIN) AF: 0.0236 AC: 1195 AN: 50662

Middle Eastern (MID) AF: 0.0461 AC: 139 AN: 3016

European-Non Finnish (NFE) AF: 0.0311 AC: 16441 AN: 528890

Other (OTH) AF: 0.0362 AC: 1413 AN: 39058

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

African (AFR) AF: 0.00674 AC: 280 AN: 41566

American (AMR) AF: 0.0178 AC: 272 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0441 AC: 153 AN: 3470

East Asian (EAS) AF: 0.0595 AC: 307 AN: 5160

South Asian (SAS) AF: 0.122 AC: 589 AN: 4828

European-Finnish (FIN) AF: 0.0192 AC: 204 AN: 10610

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0300 AC: 2038 AN: 67986

Other (OTH) AF: 0.0318 AC: 67 AN: 2110

Alfa AF: 0.0214 Hom.: 21

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

Jun 19, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.069
DANN	Benign	0.59
PhyloP100		-1.5
PromoterAI		0.045	Neutral

Splicing

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

Other links and lift over

dbSNP: rs3739209; hg19: chr19-50364423;