rs10823829

Positions:

• chr10-71706952-T-C
• chr10-71706952-T-G

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.3009T>C​(p.Ser1003=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0637 in 1,606,624 control chromosomes in the GnomAD database, including 10,081 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (3403 hom., cov: 33)
  • Exomes 𝑓: 0.055 (6678 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.56

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=-0.81).
• BP6: Variant 10-71706952-T-C is Benign according to our data. Variant chr10-71706952-T-C is described in ClinVar as [Benign]. Clinvar id is 44111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71706952-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.56 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6	c.3009T>C	p.Ser1003=	synonymous_variant	26/70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171930.2	c.3009T>C	p.Ser1003=	synonymous_variant	26/32		NP_001165401.1
CDH23	NM_001171931.2	c.3009T>C	p.Ser1003=	synonymous_variant	26/26		NP_001165402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.3009T>C	p.Ser1003=	synonymous_variant	26/70	5	NM_022124.6	ENSP00000224721	P1

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22455 AN: 152116 Hom.: 3378 Cov.: 33

Gnomad AFR AF: 0.369

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.273

Gnomad SAS AF: 0.0911

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0287

Gnomad OTH AF: 0.130

GnomAD3 exomes AF: 0.103 AC: 24322 AN: 235186 Hom.: 2592 AF XY: 0.0936 AC XY: 11966 AN XY: 127814

Gnomad AFR exome AF: 0.373

Gnomad AMR exome AF: 0.215

Gnomad ASJ exome AF: 0.128

Gnomad EAS exome AF: 0.254

Gnomad SAS exome AF: 0.0936

Gnomad FIN exome AF: 0.00880

Gnomad NFE exome AF: 0.0305

Gnomad OTH exome AF: 0.0791

GnomAD4 exome AF: 0.0548 AC: 79771 AN: 1454390 Hom.: 6678 Cov.: 31 AF XY: 0.0548 AC XY: 39578 AN XY: 722732

Gnomad4 AFR exome AF: 0.371

Gnomad4 AMR exome AF: 0.211

Gnomad4 ASJ exome AF: 0.128

Gnomad4 EAS exome AF: 0.292

Gnomad4 SAS exome AF: 0.0957

Gnomad4 FIN exome AF: 0.0103

Gnomad4 NFE exome AF: 0.0263

Gnomad4 OTH exome AF: 0.0817

GnomAD4 genome AF: 0.148 AC: 22539 AN: 152234 Hom.: 3403 Cov.: 33 AF XY: 0.145 AC XY: 10828 AN XY: 74464

Gnomad4 AFR AF: 0.370

Gnomad4 AMR AF: 0.166

Gnomad4 ASJ AF: 0.125

Gnomad4 EAS AF: 0.272

Gnomad4 SAS AF: 0.0910

Gnomad4 FIN AF: 0.0106

Gnomad4 NFE AF: 0.0287

Gnomad4 OTH AF: 0.130

Alfa AF: 0.0659 Hom.: 1081

Bravo AF: 0.175

Asia WGS AF: 0.173 AC: 604 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	Dec 28, 2012	Ser1003Ser in Exon 26A of CDH23: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 33.2% (1436/4326) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs10823829). -
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)	May 07, 2014	- -

Usher syndrome type 1D Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive nonsyndromic hearing loss 12 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	-0.81
CADD	Benign	0.026
DANN	Benign	0.58

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: rs10823829; hg19: chr10-73466709;