rs111033289

chr10-71800740-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_022124.6(CDH23):c.7467C>T(p.Arg2489=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00593 in 1,613,816 control chromosomes in the GnomAD database, including 213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (59 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (154 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.295

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 10-71800740-C-T is Benign according to our data. Variant chr10-71800740-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 46031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71800740-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.295 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0821 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.7467C>T	p.Arg2489=	synonymous_variant	53/70	ENST00000224721.12
CDH23	NM_001171933.1	c.747C>T	p.Arg249=	synonymous_variant	6/23
CDH23	NM_001171934.1	c.747C>T	p.Arg249=	synonymous_variant	6/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.7467C>T	p.Arg2489=	synonymous_variant	53/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes AF: 0.0177 AC: 2694 AN: 152092 Hom.: 60 Cov.: 32

Gnomad AFR AF: 0.0433

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0154

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.0894

Gnomad SAS AF: 0.0104

Gnomad FIN AF: 0.00462

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.0121 AC: 3016 AN: 249090 Hom.: 61 AF XY: 0.0106 AC XY: 1432 AN XY: 135138

Gnomad AFR exome AF: 0.0431

Gnomad AMR exome AF: 0.0118

Gnomad ASJ exome AF: 0.00418

Gnomad EAS exome AF: 0.0848

Gnomad SAS exome AF: 0.00465

Gnomad FIN exome AF: 0.00311

Gnomad NFE exome AF: 0.00104

Gnomad OTH exome AF: 0.00843

GnomAD4 exome AF: 0.00471 AC: 6877 AN: 1461606 Hom.: 154 Cov.: 31 AF XY: 0.00450 AC XY: 3271 AN XY: 727068

Gnomad4 AFR exome AF: 0.0431

Gnomad4 AMR exome AF: 0.0134

Gnomad4 ASJ exome AF: 0.00398

Gnomad4 EAS exome AF: 0.0720

Gnomad4 SAS exome AF: 0.00568

Gnomad4 FIN exome AF: 0.00356

Gnomad4 NFE exome AF: 0.000515

Gnomad4 OTH exome AF: 0.0100

GnomAD4 genome AF: 0.0177 AC: 2691 AN: 152210 Hom.: 59 Cov.: 32 AF XY: 0.0180 AC XY: 1338 AN XY: 74414

Gnomad4 AFR AF: 0.0432

Gnomad4 AMR AF: 0.0154

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.0888

Gnomad4 SAS AF: 0.0104

Gnomad4 FIN AF: 0.00462

Gnomad4 NFE AF: 0.000985

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00660 Hom.: 56

Bravo AF: 0.0200

Asia WGS AF: 0.0610 AC: 211 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.00107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 12, 2011	Arg2489Arg in exon 53 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 and is listed is dbSNP (rs111033289) with a frequency of 15% ( 18/120 chromosomes) in the East Asian population and 3.9% (49/1256 chromosomes) in the general population. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 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. -

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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Autosomal recessive nonsyndromic hearing loss 12 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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	-0.25
Cadd	Benign	7.2
Dann	Benign	0.62

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: rs111033289; hg19: chr10-73560497; COSMIC: COSV56452587;