rs181255269

Positions:

chr10-71694233-C-T

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.2263C>T (p.His755Tyr) variant in CDH23 is 0.73% (248/30558) for South Asian chromosomes by gnomAD v2.1.1, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). Of note, this variant was reported in 2 individuals with Usher syndrome, though without any evidence of pathogenicity (PM3 not met; PMID:18429043, 21569298). 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). 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/exons	MANE	Protein
CDH23	NM_022124.6 linkuse as main transcript	c.2263C>T	p.His755Tyr	missense_variant	21/70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171930.2 linkuse as main transcript	c.2263C>T	p.His755Tyr	missense_variant	21/32		NP_001165401.1
CDH23	NM_001171931.2 linkuse as main transcript	c.2263C>T	p.His755Tyr	missense_variant	21/26		NP_001165402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 linkuse as main transcript	c.2263C>T	p.His755Tyr	missense_variant	21/70	5	NM_022124.6	ENSP00000224721	P1	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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2019	This variant is associated with the following publications: (PMID: 30245029, 30718709, 21228398, 18429043, 22135276, 25474345, 22995991, 21569298) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	CDH23: BS1 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 05, 2022	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 30, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 15, 2023	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 17, 2015	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). -

Autosomal recessive nonsyndromic hearing loss 12

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 11, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Retinitis pigmentosa

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

Usher syndrome type 1

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 15, 2020

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 13, 2022

- -

Non-Syndromic Hereditary Hearing Impairment

Benign:1

Likely benign, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

- -

Nonsyndromic genetic hearing loss

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Jan 15, 2020

The filtering allele frequency of the c.2263C>T (p.His755Tyr) variant in CDH23 is 0.73% (248/30558) for South Asian chromosomes by gnomAD v2.1.1, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). Of note, this variant was reported in 2 individuals with Usher syndrome, though without any evidence of pathogenicity (PM3 not met; PMID: 18429043, 21569298). 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). -

Usher syndrome type 1D

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

May 18, 2021

- -

Retinitis pigmentosa-deafness syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

Aug 22, 2023

- -

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;.;.;.

MutationTaster

Benign

1.0

D;D

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