Genetic Variant ENST00000636840.1:c.57+520_57+521insG (chr19-49861087-G-GC) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBA1

The ENST00000636840.1(PNKP):c.57+520_57+521insG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0378 in 677,362 control chromosomes in the GnomAD database, including 914 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.026 ( 93 hom., cov: 32)

Exomes 𝑓: 0.041 ( 821 hom. )

Consequence

PNKP
ENST00000636840.1 intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.500

Publications

1 publications found

Variant links:

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

PNKP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP6

Variant 19-49861087-G-GC is Benign according to our data. Variant chr19-49861087-G-GC is described in ClinVar as [Likely_benign]. Clinvar id is 1208797.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNKP	NM_007254.4 link	c.160_161insG		downstream_gene_variant		ENST00000322344.8	NP_009185.2	Q96T60-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNKP	ENST00000322344.8 link	c.160_161insG		downstream_gene_variant		1	NM_007254.4	ENSP00000323511.2		Q96T60-1

Frequencies

GnomAD3 genomes

AF:

0.0262

AC:

3988

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00678

Gnomad AMI

AF:

0.0650

Gnomad AMR

AF:

0.0181

Gnomad ASJ

AF:

0.0441

Gnomad EAS

AF:

0.0591

Gnomad SAS

AF:

0.121

Gnomad FIN

AF:

0.0192

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0301

Gnomad OTH

AF:

0.0282

GnomAD4 exome

AF:

0.0412

AC:

21635

AN:

525090

Hom.:

821

AF XY:

0.0453

AC XY:

12819

AN XY:

282670

show subpopulations

African (AFR)

AF:

0.00748

AC:

110

AN:

14710

American (AMR)

AF:

0.0118

AC:

381

AN:

32288

Ashkenazi Jewish (ASJ)

AF:

0.0435

AC:

692

AN:

15914

East Asian (EAS)

AF:

0.0727

AC:

2447

AN:

33642

South Asian (SAS)

AF:

0.117

AC:

6487

AN:

55262

European-Finnish (FIN)

AF:

0.0233

AC:

792

AN:

34014

Middle Eastern (MID)

AF:

0.0440

AC:

AN:

2114

European-Non Finnish (NFE)

AF:

0.0312

AC:

9610

AN:

308182

Other (OTH)

AF:

0.0353

AC:

1023

AN:

28964

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1159

2318

3478

4637

5796

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0262

AC:

3996

AN:

152272

Hom.:

Cov.:

AF XY:

0.0265

AC XY:

1974

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.00676

AC:

281

AN:

41554

American (AMR)

AF:

0.0181

AC:

277

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0441

AC:

153

AN:

3472

East Asian (EAS)

AF:

0.0592

AC:

306

AN:

5170

South Asian (SAS)

AF:

0.121

AC:

583

AN:

4818

European-Finnish (FIN)

AF:

0.0192

AC:

204

AN:

10618

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0301

AC:

2047

AN:

68016

Other (OTH)

AF:

0.0322

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

187

375

562

750

937

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0239

Hom.:

Bravo

AF:

0.0230

Asia WGS

AF:

0.122

AC:

422

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jun 14, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.50

Splicing

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

Publications

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ENST00000636840.1:c.57+520_57+521insG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over