rs200649500

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_022124.6(CDH23):c.2239C>T(p.Arg747Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 1,613,720 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R747R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 5 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:6

Conservation

PhyloP100: 3.28

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.041192442).

BP6

Variant 10-71694209-C-T is Benign according to our data. Variant chr10-71694209-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45890.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=4}. Variant chr10-71694209-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CDH23	NM_022124.6 linkuse as main transcript	c.2239C>T	p.Arg747Cys	missense_variant	21/70	ENST00000224721.12
CDH23	NM_001171930.2 linkuse as main transcript	c.2239C>T	p.Arg747Cys	missense_variant	21/32
CDH23	NM_001171931.2 linkuse as main transcript	c.2239C>T	p.Arg747Cys	missense_variant	21/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12 linkuse as main transcript	c.2239C>T	p.Arg747Cys	missense_variant	21/70	5	NM_022124.6	P1	Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.00127

AC:

193

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000773

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00212

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00110

AC:

273

AN:

248988

Hom.:

AF XY:

0.00108

AC XY:

146

AN XY:

135114

show subpopulations

Gnomad AFR exome

AF:

0.000582

Gnomad AMR exome

AF:

0.000464

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.000187

Gnomad NFE exome

AF:

0.00205

Gnomad OTH exome

AF:

0.000827

GnomAD4 exome

AF:

0.00210

AC:

3065

AN:

1461562

Hom.:

Cov.:

AF XY:

0.00209

AC XY:

1523

AN XY:

727060

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.000626

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.000188

Gnomad4 NFE exome

AF:

0.00261

Gnomad4 OTH exome

AF:

0.00149

GnomAD4 genome

AF:

0.00127

AC:

193

AN:

152158

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.000771

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.00212

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00195

Hom.:

Bravo

AF:

0.00133

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.000241

AC:

ESP6500EA

AF:

0.00250

AC:

ExAC

AF:

0.00112

AC:

135

EpiCase

AF:

0.00224

EpiControl

AF:

0.00213

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 16, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2020	This variant is associated with the following publications: (PMID: 21436283, 24875298, 23804846) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	CDH23: BS1:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 12, 2017	The p.Arg747Cys variant (rs200649500) has been previously identified in a hearing loss cohort (Shearer et al. 2013) but was not identified in a patient with 2nd pathogenic variant of CDH23. This variant has been reported to ClinVar (Variation ID: 45890). The p.Arg747Cys variant is listed in the NHLBI GO Exome Sequencing Project with an overall population frequency of 0.18 percent (identified on 22 out of 12,542 chromosomes) and is listed in the Genome Aggregation Database (gnomAD) with a European (Non-Finnish) population frequency of 0.20 percent (identified on 247 out of 126,652 chromosomes, including 1 homozygote). The arginine at position 747 is highly conserved, up to Zebrafish (considering 12 species) (Alamut v2.10) and computational analyses of the effects of the p.Arg747Cys variant on protein structure and function predict a deleterious effect (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: probably damaging). Altogether, there is not enough evidence to classify the p.Arg747Cys variant with certainty. -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The CDH23 p.Arg747Cys variant was identified in 1 of 260 proband chromosomes (frequency: 0.00385) from individuals with nonsyndromic hearing loss and was present in 1 of 18 control chromosomes (frequency: 0.056) from healthy individuals (Vona_2014_PMID:24875298; Shearer_2013_PMID:23804846). The variant was identified in dbSNP (ID: rs200649500) and ClinVar (classified as uncertain significance by Illumina and ARUP Laboratories, and as likely benign by Laboratory for Molecular Medicine). Laboratory for Molecular Medicine reported this variant in an individual with Usher syndrome who carried another pathogenic CDH23 variant in cis, as well as in other individuals with alternate explanations for their hearing loss. The variant was identified in control databases in 304 of 280334 chromosomes (1 homozygous) at a frequency of 0.001084 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 255 of 128328 chromosomes (freq: 0.001987), Other in 6 of 7134 chromosomes (freq: 0.000841), African in 16 of 24150 chromosomes (freq: 0.000663), Latino in 16 of 35354 chromosomes (freq: 0.000453), South Asian in 7 of 30590 chromosomes (freq: 0.000229) and European (Finnish) in 4 of 24894 chromosomes (freq: 0.000161), but was not observed in the Ashkenazi Jewish or East Asian populations. The p.Arg747 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Pituitary adenoma 5, multiple types

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Sep 16, 2019

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3. -

Usher syndrome type 1

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 15, 2020

- -

Usher syndrome type 1D

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Autosomal recessive nonsyndromic hearing loss 12

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 18, 2017

p.Arg747Cys in exon 21 of CDH23: This variant is not expected to have clinical s ignificance because it has been identified in 0.2% (247/126652) of European chro mosomes including one homozygote by the Genome Aggregation Database (gnomAD, htt p://gnomad.broadinstitute.org; dbSNP rs200649500). It has been observed in 4 ind ividuals with alternate explanations for their hearing loss (Roux 2011, LMM Data ), including 1 individual who had a pathogenic truncating CDH23 variant in cis w ith this variant (https://grenada.lumc.nl: Patient ID FR0145311510; Roux 2011). This variant has also been observed in 5 additional individuals with hearing los s; however, a variant affecting the remaining copy of CDH23 was not identified ( Shearer 2013, LMM Data). In summary, given its relatively high frequency in the general population, multiple reports of the variant in individuals with alterna te etiologies, its presence in cis with a pathogenic CDH23 variant, and the fact that it has never been observed in trans with a clearly pathogenic CDH23 varian t in affected individuals, this variant is likely benign. -

CDH23-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Uncertain

0.035

BayesDel_noAF

Pathogenic

0.28

Cadd

Uncertain

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.097

T;T;T;.;T;.

Eigen

Uncertain

0.32

Eigen_PC

Benign

0.20

FATHMM_MKL

Benign

0.64

LIST_S2

Uncertain

0.97

D;D;D;D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.041

T;T;T;T;T;T

MetaSVM

Uncertain

-0.28

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.74

Sift4G

Uncertain

0.0060

D;D;.;D;D;.

Polyphen

1.0

.;.;D;.;.;.

Vest4

0.94

MVP

0.64

ClinPred

0.055

GERP RS

4.6

Varity_R

0.31

gMVP

0.70

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