rs376497158

Variant names:

• chr10-71810507-G-A
• rs376497158
• NM_022124.6:c.9015G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-71810507-G-A
• chr10-71810507-G-C
• chr10-71810507-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_022124.6(CDH23):​c.9015G>A​(p.Ala3005Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00502 in 1,613,974 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0041 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (28 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: -0.916

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]

LOC124902446 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 10-71810507-G-A is Benign according to our data. Variant chr10-71810507-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46065.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=4, Uncertain_significance=2}. Variant chr10-71810507-G-A is described in Lovd as [Benign]. Variant chr10-71810507-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.916 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00413 (629/152294) while in subpopulation NFE AF= 0.00548 (373/68014). AF 95% confidence interval is 0.00502. There are 4 homozygotes in gnomad4. There are 318 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.9015G>A	p.Ala3005Ala	synonymous_variant	Exon 62 of 70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171933.1	c.2295G>A	p.Ala765Ala	synonymous_variant	Exon 15 of 23		NP_001165404.1
CDH23	NM_001171934.1	c.2295G>A	p.Ala765Ala	synonymous_variant	Exon 15 of 22		NP_001165405.1
LOC124902446	XR_007062185.1	n.1386C>T		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.9015G>A	p.Ala3005Ala	synonymous_variant	Exon 62 of 70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes AF: 0.00413 AC: 629 AN: 152176 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00384

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00550

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00369 AC: 919 AN: 249266 Hom.: 5 AF XY: 0.00384 AC XY: 519 AN XY: 135246

Gnomad AFR exome AF: 0.00491

Gnomad AMR exome AF: 0.00385

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00379

Gnomad FIN exome AF: 0.000325

Gnomad NFE exome AF: 0.00470

Gnomad OTH exome AF: 0.00743

GnomAD4 exome AF: 0.00511 AC: 7471 AN: 1461680 Hom.: 28 Cov.: 31 AF XY: 0.00505 AC XY: 3669 AN XY: 727126

Gnomad4 AFR exome AF: 0.00341

Gnomad4 AMR exome AF: 0.00398

Gnomad4 ASJ exome AF: 0.000689

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00359

Gnomad4 FIN exome AF: 0.000449

Gnomad4 NFE exome AF: 0.00588

Gnomad4 OTH exome AF: 0.00455

GnomAD4 genome AF: 0.00413 AC: 629 AN: 152294 Hom.: 4 Cov.: 32 AF XY: 0.00427 AC XY: 318 AN XY: 74454

Gnomad4 AFR AF: 0.00382

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00548

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00269 Hom.: 0

Bravo AF: 0.00404

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00398

EpiControl AF: 0.00338

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Apr 18, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ala3005Ala in exon 62 of CDH23: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located near a splice junction, has been identified in 0.4% (30/6796) of European American ch romosomes from a broad population by the NHLBI Exome sequencing project (http:// evs.gs.washington.edu/EVS/; dbSNP rs41304884), and is reported as benign in one publication (Astuto 2002). -

Apr 16, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CDH23: BP4, BP7, BS2 -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1D Uncertain:1

Jan 13, 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. -

Autosomal recessive nonsyndromic hearing loss 12 Uncertain:1

Jan 13, 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. -

Usher syndrome type 1 Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	6.7
DANN	Benign	0.70

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: rs376497158; hg19: chr10-73570264; COSMIC: COSV105842320;