chr10-71705055-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_022124.6(CDH23):c.2878G>A(p.Glu960Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00368 in 1,612,632 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0029 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0038 ( 17 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:12

Conservation

PhyloP100: 2.73

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:

ENSG00000300551 (HGNC:):

ENSG00000300551 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 14 uncertain in NM_022124.6

BP4

Computational evidence support a benign effect (MetaRNN=0.010432005).

BP6

Variant 10-71705055-G-A is Benign according to our data. Variant chr10-71705055-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45904.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00293 (446/152304) while in subpopulation NFE AF = 0.00468 (318/68010). AF 95% confidence interval is 0.00425. There are 2 homozygotes in GnomAd4. There are 203 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6 link	c.2878G>A	p.Glu960Lys	missense_variant	Exon 25 of 70	ENST00000224721.12	NP_071407.4	Q9H251-1Q6P152
CDH23	NM_001171930.2 link	c.2878G>A	p.Glu960Lys	missense_variant	Exon 25 of 32		NP_001165401.1	Q9H251A0A087WYR8Q6P152
CDH23	NM_001171931.2 link	c.2878G>A	p.Glu960Lys	missense_variant	Exon 25 of 26		NP_001165402.1	Q9H251Q8N5B3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 link	c.2878G>A	p.Glu960Lys	missense_variant	Exon 25 of 70	5	NM_022124.6	ENSP00000224721.9		Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.00294

AC:

447

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000869

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.00438

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00469

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00302

AC:

742

AN:

245864

AF XY:

0.00306

show subpopulations

Gnomad AFR exome

AF:

0.000597

Gnomad AMR exome

AF:

0.00369

Gnomad ASJ exome

AF:

0.000201

Gnomad EAS exome

AF:

0.0000560

Gnomad FIN exome

AF:

0.00135

Gnomad NFE exome

AF:

0.00499

Gnomad OTH exome

AF:

0.00350

GnomAD4 exome

AF:

0.00376

AC:

5490

AN:

1460328

Hom.:

Cov.:

AF XY:

0.00373

AC XY:

2711

AN XY:

726500

show subpopulations

African (AFR)

AF:

0.000568

AC:

AN:

33474

American (AMR)

AF:

0.00349

AC:

156

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.000230

AC:

AN:

26112

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00161

AC:

AN:

52156

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00454

AC:

5044

AN:

1111826

Other (OTH)

AF:

0.00293

AC:

177

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

344

688

1033

1377

1721

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

352

528

704

880

<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:

0.00293

AC:

446

AN:

152304

Hom.:

Cov.:

AF XY:

0.00273

AC XY:

203

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.000866

AC:

AN:

41570

American (AMR)

AF:

0.00438

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00468

AC:

318

AN:

68010

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

105

131

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00402

Hom.:

Bravo

AF:

0.00315

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.000964

AC:

ESP6500EA

AF:

0.00418

AC:

ExAC

AF:

0.00314

AC:

380

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00485

EpiControl

AF:

0.00510

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:6

Oct 08, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 18429043, 32707200) -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 03, 2021

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 12, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CDH23: BP4, BS2 -

not specified

Benign:3

Jun 11, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Glu960Lys variant in CDH23: 0.4% (35/8368) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs111033458). -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 12, 2022

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.2878G>A (p.Glu960Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.003 in 245864 control chromosomes, predominantly at a frequency of 0.005 within the Non-Finnish European subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.6 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 Non-Finnish European origin. Although reported in the literature, to our knowledge, no penetrant association of c.2878G>A in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories report a majority consensus as benign. Based on the evidence outlined above, the variant was classified as benign. -

Autosomal recessive nonsyndromic hearing loss 12

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

CDH23-related disorder

Benign:1

Oct 04, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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). -

Usher syndrome type 1D

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Usher syndrome type 1

Benign:1

Apr 15, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0068

T;T;T;.;T;.

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.090

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.68

T;T;T;T;T;T

M_CAP

Benign

0.0026

MetaRNN

Benign

0.010

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.14

.;.;N;.;.;.

PhyloP100

2.7

PrimateAI

Benign

0.38

REVEL

Benign

0.091

Sift4G

Benign

0.60

T;T;.;T;T;.

Polyphen

0.0040

.;.;B;.;.;.

Vest4

0.43

MVP

0.72

ClinPred

0.014

GERP RS

4.6

Varity_R

0.066

gMVP

0.39

Mutation Taster

=90/10

polymorphism

(source)

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

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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