rs76601590

chr10-71702048-G-Achr10-71702048-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_022124.6(CDH23):c.2424G>A(p.Gly808=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0152 in 1,613,768 control chromosomes in the GnomAD database, including 1,980 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (221 hom., cov: 32)
  • Exomes 𝑓: 0.015 (1759 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.16

Genes affected

CDH23 (HGNC:13733): (cadherin related 23) This gene is a member of the cadherin superfamily, whose genes encode calcium dependent cell-cell adhesion glycoproteins. The encoded protein is thought to be involved in stereocilia organization and hair bundle formation. The gene is located in a region containing the human deafness loci DFNB12 and USH1D. Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of this cadherin-like gene. Upregulation of this gene may also be associated with breast cancer. Alternative splice variants encoding different isoforms have been described. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 10-71702048-G-A is Benign according to our data. Variant chr10-71702048-G-A is described in ClinVar as [Benign]. Clinvar id is 45897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71702048-G-A is described in Lovd as [Benign]. Variant chr10-71702048-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.16 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.2424G>A	p.Gly808=	synonymous_variant	23/70	ENST00000224721.12
CDH23	NM_001171930.2	c.2424G>A	p.Gly808=	synonymous_variant	23/32
CDH23	NM_001171931.2	c.2424G>A	p.Gly808=	synonymous_variant	23/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.2424G>A	p.Gly808=	synonymous_variant	23/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes AF: 0.0204 AC: 3106 AN: 152172 Hom.: 215 Cov.: 32

Gnomad AFR AF: 0.00287

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.0228

Gnomad FIN AF: 0.00687

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00184

Gnomad OTH AF: 0.0234

GnomAD3 exomes AF: 0.0439 AC: 10921 AN: 248978 Hom.: 1000 AF XY: 0.0366 AC XY: 4948 AN XY: 135136

Gnomad AFR exome AF: 0.00207

Gnomad AMR exome AF: 0.183

Gnomad ASJ exome AF: 0.0152

Gnomad EAS exome AF: 0.176

Gnomad SAS exome AF: 0.0228

Gnomad FIN exome AF: 0.00520

Gnomad NFE exome AF: 0.00227

Gnomad OTH exome AF: 0.0324

GnomAD4 exome AF: 0.0146 AC: 21391 AN: 1461478 Hom.: 1759 Cov.: 32 AF XY: 0.0141 AC XY: 10265 AN XY: 727022

Gnomad4 AFR exome AF: 0.00215

Gnomad4 AMR exome AF: 0.176

Gnomad4 ASJ exome AF: 0.0145

Gnomad4 EAS exome AF: 0.201

Gnomad4 SAS exome AF: 0.0242

Gnomad4 FIN exome AF: 0.00532

Gnomad4 NFE exome AF: 0.00117

Gnomad4 OTH exome AF: 0.0220

GnomAD4 genome AF: 0.0206 AC: 3130 AN: 152290 Hom.: 221 Cov.: 32 AF XY: 0.0228 AC XY: 1701 AN XY: 74454

Gnomad4 AFR AF: 0.00286

Gnomad4 AMR AF: 0.106

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.190

Gnomad4 SAS AF: 0.0230

Gnomad4 FIN AF: 0.00687

Gnomad4 NFE AF: 0.00184

Gnomad4 OTH AF: 0.0250

Alfa AF: 0.00580 Hom.: 23

Bravo AF: 0.0301

Asia WGS AF: 0.0870 AC: 301 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 12, 2009	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 05, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 08, 2013	- -

Usher syndrome type 1D Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Autosomal recessive nonsyndromic hearing loss 12 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

Usher syndrome type 1 Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	3.9
Dann	Benign	0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs76601590; hg19: chr10-73461805; COSMIC: COSV54936484;