rs202052174

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM1BP4_ModerateBS1_Supporting

The NM_022124.6(CDH23):c.7823G>A(p.Arg2608His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000686 in 1,600,450 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2608C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00057 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00070 ( 1 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:13B:2O:1

Conservation

PhyloP100: 7.78

Publications

11 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 12
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Usher syndrome type 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Usher syndrome type 1D
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CDH23 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_022124.6

BP4

Computational evidence support a benign effect (MetaRNN=0.1011363).

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000572 (87/152094) while in subpopulation AMR AF = 0.00144 (22/15282). AF 95% confidence interval is 0.000975. There are 0 homozygotes in GnomAd4. There are 45 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CDH23	NM_022124.6 link	c.7823G>A	p.Arg2608His	missense_variant	Exon 55 of 70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171933.1 link	c.1103G>A	p.Arg368His	missense_variant	Exon 8 of 23		NP_001165404.1
CDH23	NM_001171934.1 link	c.1103G>A	p.Arg368His	missense_variant	Exon 8 of 22		NP_001165405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 link	c.7823G>A	p.Arg2608His	missense_variant	Exon 55 of 70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes

AF:

0.000572

AC:

AN:

151976

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000218

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000661

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000677

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.000667

AC:

150

AN:

224942

AF XY:

0.000631

show subpopulations

Gnomad AFR exome

AF:

0.000232

Gnomad AMR exome

AF:

0.000763

Gnomad ASJ exome

AF:

0.000104

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000541

Gnomad NFE exome

AF:

0.00107

Gnomad OTH exome

AF:

0.000356

GnomAD4 exome

AF:

0.000698

AC:

1011

AN:

1448356

Hom.:

Cov.:

AF XY:

0.000673

AC XY:

484

AN XY:

719238

show subpopulations

African (AFR)

AF:

0.000243

AC:

AN:

32920

American (AMR)

AF:

0.000993

AC:

AN:

43322

Ashkenazi Jewish (ASJ)

AF:

0.0000387

AC:

AN:

25822

East Asian (EAS)

AF:

0.00

AC:

AN:

38654

South Asian (SAS)

AF:

0.0000598

AC:

AN:

83562

European-Finnish (FIN)

AF:

0.000516

AC:

AN:

52294

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.000806

AC:

891

AN:

1106132

Other (OTH)

AF:

0.000501

AC:

AN:

59898

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

109

163

218

272

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000572

AC:

AN:

152094

Hom.:

Cov.:

AF XY:

0.000605

AC XY:

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41482

American (AMR)

AF:

0.00144

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.000661

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000677

AC:

AN:

67978

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000726

Hom.:

Bravo

AF:

0.000820

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000953

AC:

ExAC

AF:

0.000844

AC:

102

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:13Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:4Benign:2

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Likely pathogenic

Review Status:flagged submission

Collection Method:clinical testing

- -

Aug 11, 2022

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 10, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 05, 2021

GeneDx

Significance:Likely benign

Review Status:flagged submission

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 16963483, 21940737, 12786748, 28847902, 27018795, 12075507, 19683999, 21174530, 26969326, 30459346, 33576794) -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome type 1D

Uncertain:2

Apr 08, 2021

Ocular Genomics Institute, Massachusetts Eye and Ear

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

The CDH23 c.7823G>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PP3. Based on this evidence we have classified this variant as Variant of Uncertian Significance. -

Jul 14, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 12

Uncertain:2

Dec 21, 2021

UAEU Genomics Laboratory, United Arab Emirates University

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

The missense variant NM_022124.6(CDH23):c.7823G>A (p.Arg2608His) has been reported in compound heterozygous state in multiple publications in individuals affected with nonsyndromic deafness (PMID: 12075507, PubMed: 26969326, PMID: 27018795) Usher syndrome (PMID: 33576794, PMID: 19683999) in at least 4 individuals with a likely pathogenic or rare allele (PubMed: 33576794, PMID: 30459346, PMID: 12075507, PubMed: 26969326). This variant was also present in heterozygous state in individuals affected with non-syndromic sensorineural hearing loss (PMID: 30459346, PMID: 27018795). Another variant causing a different amino acid change (p.Arg2608Cys)) has been reported in an individual with nonsyndromic recessive deafness, who also had another variant in the same gene in homozygous state (PubMeD: 26226137). The p.Arg2608His variant is observed in 107/99,932 (0.1071%) alleles from individuals of gnomAD Non Finnish European background in gnomAD database, which is higher than that specified by the hearing loss expert working group (PubMed: 30311386). Computational prediction tools and conservation analysis indicate that this change could be deleterious. Structural modeling studies indicated that this variant affect one of the outward facing residues in the CDH23 extracellular domain and might affect intramolecular hydrogen bonding and cis- dimer formation (PMID: 30033219). In summary, though the variant has been reported frequently patients with disease, the available evidence is insufficient to classify this variant with certainty. For these reasons, this variant has been classified as Uncertain significance. -

Jul 14, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Pathogenic:1

Jan 01, 2023

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Jun 23, 2025

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CDH23 c.7823G>A (p.Arg2608His) results in a non-conservative amino acid change located in the cadherin repeat region (IPR002126) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00067 in 224942 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CDH23 causing Usher Syndrome (0.00067 vs 0.0032), allowing no conclusion about variant significance. c.7823G>A has been observed in compound heterozygous state with a second pathogenic variant (though the phase was not specified in most cases) in individuals affected with Usher Syndrome (Jaijo_2009, Colombo_2021), nonsyndromic hearing loss (Astuto_2002, Wu_2016), and retinal disease (Zampaglione_2022). On the other hand, the variant has been reported in homozygous state in a patient affected with retinal disease (without hearing loss), who carried a homozygous pathogenic variant in another gene, which could explain the phenotype (Ortube_2014). The variant has been also reported in heterozygosity in affected individuals without detected second allele variant (Fuster-Garcia_2018, Mansard_2021, Wu_2016, Sloan-Heggen_2016). In one of these cases, co-occurring pathogenic variants could explain the phenotype (Mansard_2021). In many of the reported cases, the CDH23 gene was not completely sequenced, or other genes and large rearrangements were not assessed, thus these reports do not provide conclusive evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 12075507, 27018795, 26969326, 19683999, 30459346, 33576794, 34948090, 24444108, 36460718, 34906470). ClinVar contains an entry for this variant (Variation ID: 46040). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Neurodevelopmental abnormality

Uncertain:1

Apr 03, 2020

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Pituitary adenoma 5, multiple types

Uncertain:1

Jul 06, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinitis pigmentosa-deafness syndrome

Uncertain:1

May 28, 2019

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Rare genetic deafness

Uncertain:1

Jun 23, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg2608His variant in CDH23 has been reported in 0.1% (7/6982) of chromosomes from probands with either hearing loss or Usher syndrome, at least one of whom had an alternate genetic cause for their disease (Astuto 2002, Jaijo 2010; Malm 2011, LMM data). However, this variant has also been identified in 0.1% (116/115288) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org), which suggests that the variant is unlikely to be causative for disease. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while the clinical significance of p.Arg2608His is uncertain, these data suggest that it is more likely benign. ACMG/AMP criteria: BS1_Supporting, PP3. -

Autosomal recessive nonsyndromic hearing loss 12;C1832845:Usher syndrome type 1D

Other:1

GenomeConnect - Invitae Patient Insights Network

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Uncertain significance and reported on 01-06-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.029

T;T;.;.

Eigen

Pathogenic

0.68

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Benign

0.032

MetaRNN

Benign

0.10

T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.42

.;N;.;.

PhyloP100

7.8

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-2.1

.;.;.;N

REVEL

Uncertain

0.44

Sift

Benign

0.080

.;.;.;T

Sift4G

Uncertain

0.0020

D;.;D;D

Polyphen

1.0

.;D;.;.

Vest4

0.66

MVP

0.74

MPC

0.45

ClinPred

0.14

GERP RS

4.5

Varity_R

0.54

gMVP

0.59

Mutation Taster

=23/77

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over