rs181255269

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The variant NM_022124.6:c.2263C>T in CDH23 is a missense variant predicted to cause substitution of histidine by tyrosine at amino acid 755 (p.His755Tyr). The highest population minor allele frequency in gnomAD v4.1.0 is 0.008578 (781/91042 alleles, 11 homozygotes) for the South Asian population, which is higher than the ClinGen Hearing Loss CDH23 threshold (≥0.005) for BA1, and therefore meets this criterion (BA1). The REVEL computational prediction analysis tool produced a score of 0.211, which meets no codes. This variant was reported in 2 individuals with Usher syndrome and one with Retinitis Pigmentosa, though without any evidence of pathogenicity (PM3 not met; PMIDs: 18429043, 21569298, 30718709). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1. (ClinGen Hearing Loss VCEP specifications version 2; 12/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA137317/MONDO:0019497/005

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 13 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Benign reviewed by expert panel P:1U:2B:18

Conservation

PhyloP100: 5.96

Variant links:

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]

CDH23 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6 link	c.2263C>T	p.His755Tyr	missense_variant	Exon 21 of 70	ENST00000224721.12	NP_071407.4	Q9H251-1Q6P152
CDH23	NM_001171930.2 link	c.2263C>T	p.His755Tyr	missense_variant	Exon 21 of 32		NP_001165401.1	Q9H251A0A087WYR8Q6P152
CDH23	NM_001171931.2 link	c.2263C>T	p.His755Tyr	missense_variant	Exon 21 of 26		NP_001165402.1	Q9H251Q8N5B3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 link	c.2263C>T	p.His755Tyr	missense_variant	Exon 21 of 70	5	NM_022124.6	ENSP00000224721.9		Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.00109

AC:

166

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00892

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000970

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00218

AC:

542

AN:

248490

Hom.:

AF XY:

0.00268

AC XY:

362

AN XY:

134874

show subpopulations

Gnomad AFR exome

AF:

0.000130

Gnomad AMR exome

AF:

0.000696

Gnomad ASJ exome

AF:

0.00657

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.00812

Gnomad FIN exome

AF:

0.000613

Gnomad NFE exome

AF:

0.00156

Gnomad OTH exome

AF:

0.00199

GnomAD4 exome

AF:

0.00145

AC:

2118

AN:

1460878

Hom.:

Cov.:

AF XY:

0.00171

AC XY:

1246

AN XY:

726652

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000828

Gnomad4 ASJ exome

AF:

0.00685

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00856

Gnomad4 FIN exome

AF:

0.000622

Gnomad4 NFE exome

AF:

0.000839

Gnomad4 OTH exome

AF:

0.00212

GnomAD4 genome

AF:

0.00109

AC:

166

AN:

152178

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

103

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00892

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.000970

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00142

Hom.:

Bravo

AF:

0.000914

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00130

AC:

ExAC

AF:

0.00226

AC:

274

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.00256

EpiControl

AF:

0.00237

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Uncertain:2Benign:18

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:9

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 05, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 06, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30245029, 30718709, 21228398, 18429043, 22135276, 25474345, 22995991, 21569298) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CDH23: BS1 -

not specified

Benign:3

Dec 17, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.His755Tyr in exon 21 of CDH23: This variant is not expected to have clinical s ignificance because it has been identified in 0.85% (136/16100) of South Asian c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs181255269). -

Aug 30, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 15, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CDH23 c.2263C>T (p.His755Tyr) results in a conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0022 in 248490 control chromosomes, predominantly at a frequency of 0.0081 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH23 causing Usher Syndrome phenotype (0.0032), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.2263C>T in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Thirteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Eight laboratories reported the variant with benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Autosomal recessive nonsyndromic hearing loss 12

Uncertain:1Benign:1

Sep 11, 2019

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa

Pathogenic:1

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Usher syndrome type 1

Uncertain:1

Apr 15, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 12;C1832845:Usher syndrome type 1D;C4539685:Pituitary adenoma 5, multiple types

Benign:1

Apr 13, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Non-Syndromic Hereditary Hearing Impairment

Benign:1

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Nonsyndromic genetic hearing loss

Benign:1

Dec 18, 2024

ClinGen Hearing Loss Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The variant NM_022124.6:c.2263C>T in CDH23 is a missense variant predicted to cause substitution of histidine by tyrosine at amino acid 755 (p.His755Tyr). The highest population minor allele frequency in gnomAD v4.1.0 is 0.008578 (781/91042 alleles, 11 homozygotes) for the South Asian population, which is higher than the ClinGen Hearing Loss CDH23 threshold (≥0.005) for BA1, and therefore meets this criterion (BA1). The REVEL computational prediction analysis tool produced a score of 0.211, which meets no codes. This variant was reported in 2 individuals with Usher syndrome and one with Retinitis Pigmentosa, though without any evidence of pathogenicity (PM3 not met; PMIDs: 18429043, 21569298, 30718709). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1. (ClinGen Hearing Loss VCEP specifications version 2; 12/18/2024). -

Usher syndrome type 1D

Benign:1

May 18, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa-deafness syndrome

Benign:1

Aug 22, 2023

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.0

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0067

T;T;T;.;T;.

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.95

D;D;D;D;D;D

M_CAP

Benign

0.0041

MetaRNN

Benign

0.0098

T;T;T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.0

.;.;N;.;.;.

PrimateAI

Uncertain

0.63

REVEL

Benign

0.21

Sift4G

Benign

0.11

T;T;.;T;T;.

Polyphen

0.95

.;.;P;.;.;.

Vest4

0.64

MVP

0.73

ClinPred

0.048

GERP RS

5.5

Varity_R

0.50

gMVP

0.54

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over