rs185220846

Variant names:

• chr2-178460454-T-C
• rs185220846
• NM_001042702.5:c.766+8T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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:1 B:4
• Conservation: PhyloP100: -0.603
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 59

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 178339.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PJVK	NM_001042702.5	c.766+8T>C		splice_region_variant, intron_variant	Intron 6 of 6	ENST00000644580.2	NP_001036167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PJVK	ENST00000644580.2	c.766+8T>C		splice_region_variant, intron_variant	Intron 6 of 6		NM_001042702.5	ENSP00000495855.2

Frequencies

GnomAD3 genomes AF: 0.00144 AC: 219 AN: 152200 Hom.: 4 Cov.: 32

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

GnomAD2 exomes AF: 0.00285 AC: 711 AN: 249194 AF XY: 0.00374

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 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.: 46 Cov.: 29 AF XY: 0.00221 AC XY: 1599 AN XY: 724884

African (AFR) AF: 0.000239 AC: 8 AN: 33406

American (AMR) AF: 0.000559 AC: 25 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00153 AC: 40 AN: 26096

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39638

South Asian (SAS) AF: 0.0182 AC: 1567 AN: 86122

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00330 AC: 19 AN: 5758

European-Non Finnish (NFE) AF: 0.000519 AC: 575 AN: 1106982

Other (OTH) AF: 0.00243 AC: 146 AN: 60192

GnomAD4 genome AF: 0.00146 AC: 222 AN: 152318 Hom.: 5 Cov.: 32 AF XY: 0.00164 AC XY: 122 AN XY: 74488

African (AFR) AF: 0.000168 AC: 7 AN: 41574

American (AMR) AF: 0.00157 AC: 24 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.0224 AC: 108 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00112 AC: 76 AN: 68032

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000741 Hom.: 0

Bravo AF: 0.000714

Asia WGS AF: 0.0110 AC: 38 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Nov 25, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 30, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) . -

not provided Benign:2

Oct 31, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 59 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.60
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs185220846; hg19: chr2-179325181;