rs199841343

chr2-178461009-G-Achr2-178461009-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_001042702.5(PJVK):c.794G>A(p.Arg265His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000332 in 1,613,722 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R265C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (1 hom.)
• Consequence: PJVK NM_001042702.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 2.81

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03406304).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000348 (508/1461698) while in subpopulation MID AF= 0.000693 (4/5768). AF 95% confidence interval is 0.000362. There are 1 homozygotes in gnomad4_exome. There are 264 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PJVK	NM_001042702.5	c.794G>A	p.Arg265His	missense_variant	7/7	ENST00000644580.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PJVK	ENST00000644580.2	c.794G>A	p.Arg265His	missense_variant	7/7		NM_001042702.5	P1

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 27 AN: 151906 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000257 AC: 64 AN: 249444 Hom.: 0 AF XY: 0.000229 AC XY: 31 AN XY: 135356

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000353

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000348 AC: 508 AN: 1461698 Hom.: 1 Cov.: 32 AF XY: 0.000363 AC XY: 264 AN XY: 727158

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000417

Gnomad4 FIN exome AF: 0.000113

Gnomad4 NFE exome AF: 0.000392

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000178 AC: 27 AN: 152024 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74310

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000208 Hom.: 0

Bravo AF: 0.000219

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000268 AC: 1

ESP6500EA AF: 0.000975 AC: 8

ExAC AF: 0.000356 AC: 43

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 06, 2022	BP4, PM2_supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Apr 17, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 265 of the DFNB59 protein (p.Arg265His). This variant is present in population databases (rs199841343, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with DFNB59-related conditions. ClinVar contains an entry for this variant (Variation ID: 288934). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 13, 2016	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2021

The c.794G>A (p.R265H) alteration is located in exon 7 (coding exon 6) of the DFNB59 gene. This alteration results from a G to A substitution at nucleotide position 794, causing the arginine (R) at amino acid position 265 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Autosomal recessive nonsyndromic hearing loss 59 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	17
Dann	Benign	0.78
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.59	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.034	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.29	T
Polyphen		0.0050	.;B;.;B;.;.;.;B
Vest4		0.031, 0.032
MVP		0.41
MPC		0.13
ClinPred		0.015	T
GERP RS		3.3
Varity_R		0.028
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs199841343; hg19: chr2-179325736;