rs185220846

Positions:

chr2-178460454-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001042702.5(PJVK):c.766+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,608,602 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 46 hom. )

Consequence

PJVK
NM_001042702.5 splice_region, intron

Scores

Splicing: ADA: 0.0001418

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -0.603

Variant links:

Genes affected

PJVK (HGNC:29502): (pejvakin) The protein encoded by this gene is a member of the gasdermin family, a family which is found only in vertebrates. The encoded protein is required for the proper function of auditory pathway neurons. Defects in this gene are a cause of non-syndromic sensorineural deafness autosomal recessive type 59 (DFNB59). [provided by RefSeq, Dec 2008]

PJVK links:

PJVK (HGNC:):

PJVK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 2-178460454-T-C is Benign according to our data. Variant chr2-178460454-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178339.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=4}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00146 (222/152318) while in subpopulation SAS AF= 0.0224 (108/4822). AF 95% confidence interval is 0.019. There are 5 homozygotes in gnomad4. There are 122 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PJVK	NM_001042702.5 linkuse as main transcript	c.766+8T>C		splice_region_variant, intron_variant		ENST00000644580.2	NP_001036167.1	Q0ZLH3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PJVK	ENST00000644580.2 linkuse as main transcript	c.766+8T>C		splice_region_variant, intron_variant			NM_001042702.5	ENSP00000495855.2		Q0ZLH3

Frequencies

GnomAD3 genomes

AF:

0.00144

AC:

219

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0218

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00112

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00285

AC:

711

AN:

249194

Hom.:

AF XY:

0.00374

AC XY:

505

AN XY:

135196

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.000551

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0179

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00102

Gnomad OTH exome

AF:

0.00231

GnomAD4 exome

AF:

0.00164

AC:

2384

AN:

1456284

Hom.:

Cov.:

AF XY:

0.00221

AC XY:

1599

AN XY:

724884

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000559

Gnomad4 ASJ exome

AF:

0.00153

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0182

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000519

Gnomad4 OTH exome

AF:

0.00243

GnomAD4 genome

AF:

0.00146

AC:

222

AN:

152318

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

122

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0224

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00112

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000747

Hom.:

Bravo

AF:

0.000714

Asia WGS

AF:

0.0110

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 30, 2015	c.766+8T>C in Intron 06 of DFNB59: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus se quence and has been identified in 1.9% (316/16358) of South Asian chromosomes by the Exome Aggregation Consoritum (http://exac.broadinstitute.org/; rs185220846) . -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 25, 2015	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Autosomal recessive nonsyndromic hearing loss 59

Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

1.6

DANN

Benign

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00014

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over