rs74608315

chr10-71617297-G-A

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.1038G>A(p.Pro346=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,613,950 control chromosomes in the GnomAD database, including 354 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (35 hom., cov: 32)
  • Exomes 𝑓: 0.012 (319 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -8.05

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=-0.92).
• BP6: Variant 10-71617297-G-A is Benign according to our data. Variant chr10-71617297-G-A is described in ClinVar as [Benign]. Clinvar id is 44112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-8.05 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0689 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.1038G>A	p.Pro346=	synonymous_variant	11/70	ENST00000224721.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.1038G>A	p.Pro346=	synonymous_variant	11/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1671 AN: 152136 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.0455

Gnomad EAS AF: 0.0751

Gnomad SAS AF: 0.0224

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.00985

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.0181 AC: 4506 AN: 249326 Hom.: 92 AF XY: 0.0185 AC XY: 2508 AN XY: 135220

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.0182

Gnomad ASJ exome AF: 0.0473

Gnomad EAS exome AF: 0.0729

Gnomad SAS exome AF: 0.0240

Gnomad FIN exome AF: 0.000604

Gnomad NFE exome AF: 0.0107

Gnomad OTH exome AF: 0.0185

GnomAD4 exome AF: 0.0119 AC: 17387 AN: 1461696 Hom.: 319 Cov.: 31 AF XY: 0.0125 AC XY: 9054 AN XY: 727132

Gnomad4 AFR exome AF: 0.00263

Gnomad4 AMR exome AF: 0.0169

Gnomad4 ASJ exome AF: 0.0484

Gnomad4 EAS exome AF: 0.0803

Gnomad4 SAS exome AF: 0.0237

Gnomad4 FIN exome AF: 0.000768

Gnomad4 NFE exome AF: 0.00776

Gnomad4 OTH exome AF: 0.0163

GnomAD4 genome AF: 0.0110 AC: 1669 AN: 152254 Hom.: 35 Cov.: 32 AF XY: 0.0119 AC XY: 885 AN XY: 74452

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.0139

Gnomad4 ASJ AF: 0.0455

Gnomad4 EAS AF: 0.0751

Gnomad4 SAS AF: 0.0222

Gnomad4 FIN AF: 0.000942

Gnomad4 NFE AF: 0.00985

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0128 Hom.: 9

Bravo AF: 0.0125

Asia WGS AF: 0.0370 AC: 129 AN: 3478

EpiCase AF: 0.0151

EpiControl AF: 0.0130

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 07, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 09, 2013	Pro346Pro in Exon 11A of CDH23: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 0.9% (81/8568) of Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs74608315). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 12, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Usher syndrome type 1 Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Usher syndrome type 1D Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Autosomal recessive nonsyndromic hearing loss 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.16
Dann	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs74608315; hg19: chr10-73377054; COSMIC: COSV54946284;