10-71675149-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_022124.6(CDH23):c.1487G>A(p.Ser496Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 1,612,966 control chromosomes in the GnomAD database, including 60,315 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 Benign (★★).

Frequency

Genomes: 𝑓 0.27 ( 5568 hom., cov: 32)

Exomes 𝑓: 0.27 ( 54747 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.420

Publications

37 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006324768).

BP6

Variant 10-71675149-G-A is Benign according to our data. Variant chr10-71675149-G-A is described in ClinVar as Benign. ClinVar VariationId is 45875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6 link	c.1487G>A	p.Ser496Asn	missense_variant	Exon 15 of 70	ENST00000224721.12	NP_071407.4	Q9H251-1Q6P152
CDH23	NM_001171930.2 link	c.1487G>A	p.Ser496Asn	missense_variant	Exon 15 of 32		NP_001165401.1	Q9H251A0A087WYR8Q6P152
CDH23	NM_001171931.2 link	c.1487G>A	p.Ser496Asn	missense_variant	Exon 15 of 26		NP_001165402.1	Q9H251Q8N5B3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 link	c.1487G>A	p.Ser496Asn	missense_variant	Exon 15 of 70	5	NM_022124.6	ENSP00000224721.9		Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.270

AC:

41019

AN:

152038

Hom.:

5559

Cov.:

show subpopulations

Gnomad AFR

AF:

0.257

Gnomad AMI

AF:

0.241

Gnomad AMR

AF:

0.295

Gnomad ASJ

AF:

0.187

Gnomad EAS

AF:

0.269

Gnomad SAS

AF:

0.260

Gnomad FIN

AF:

0.310

Gnomad MID

AF:

0.234

Gnomad NFE

AF:

0.271

Gnomad OTH

AF:

0.273

GnomAD2 exomes

AF:

0.274

AC:

68122

AN:

249022

AF XY:

0.272

show subpopulations

Gnomad AFR exome

AF:

0.255

Gnomad AMR exome

AF:

0.306

Gnomad ASJ exome

AF:

0.188

Gnomad EAS exome

AF:

0.297

Gnomad FIN exome

AF:

0.301

Gnomad NFE exome

AF:

0.266

Gnomad OTH exome

AF:

0.264

GnomAD4 exome

AF:

0.272

AC:

396639

AN:

1460810

Hom.:

54747

Cov.:

AF XY:

0.271

AC XY:

196966

AN XY:

726734

show subpopulations

African (AFR)

AF:

0.258

AC:

8649

AN:

33472

American (AMR)

AF:

0.304

AC:

13596

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.186

AC:

4855

AN:

26130

East Asian (EAS)

AF:

0.244

AC:

9701

AN:

39690

South Asian (SAS)

AF:

0.272

AC:

23458

AN:

86236

European-Finnish (FIN)

AF:

0.306

AC:

16340

AN:

53366

Middle Eastern (MID)

AF:

0.258

AC:

1488

AN:

5766

European-Non Finnish (NFE)

AF:

0.272

AC:

302019

AN:

1111102

Other (OTH)

AF:

0.274

AC:

16533

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

13810

27620

41430

55240

69050

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10150

20300

30450

40600

50750

<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:

0.270

AC:

41072

AN:

152156

Hom.:

5568

Cov.:

AF XY:

0.272

AC XY:

20224

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.257

AC:

10656

AN:

41486

American (AMR)

AF:

0.296

AC:

4524

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.187

AC:

648

AN:

3470

East Asian (EAS)

AF:

0.269

AC:

1395

AN:

5186

South Asian (SAS)

AF:

0.260

AC:

1254

AN:

4828

European-Finnish (FIN)

AF:

0.310

AC:

3285

AN:

10592

Middle Eastern (MID)

AF:

0.235

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.271

AC:

18439

AN:

67990

Other (OTH)

AF:

0.276

AC:

583

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1572

3144

4717

6289

7861

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

434

868

1302

1736

2170

<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:

0.267

Hom.:

25058

Bravo

AF:

0.268

TwinsUK

AF:

0.256

AC:

950

ALSPAC

AF:

0.282

AC:

1088

ESP6500AA

AF:

0.230

AC:

963

ESP6500EA

AF:

0.260

AC:

2193

ExAC

AF:

0.272

AC:

32861

Asia WGS

AF:

0.261

AC:

907

AN:

3478

EpiCase

AF:

0.258

EpiControl

AF:

0.256

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 09, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome type 1D

Benign:2

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Autosomal recessive nonsyndromic hearing loss 12

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome type 1

Benign:1

Sep 16, 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

0.064

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.70

(source)

DANN

Benign

0.44

DEOGEN2

Benign

0.011

T;T;T;.;T;.

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.064

T;T;T;T;T;T

MetaRNN

Benign

0.0063

T;T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.4

.;.;L;.;.;.

PhyloP100

0.42

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-2.4

.;.;.;.;.;N

REVEL

Benign

0.070

Sift

Uncertain

0.0020

.;.;.;.;.;D

Sift4G

Benign

0.65

T;T;.;T;T;.

Polyphen

0.0

.;.;B;.;.;.

Vest4

0.056

ClinPred

0.0030

GERP RS

-0.61

Varity_R

0.047

gMVP

0.37

Mutation Taster

=97/3

polymorphism (auto)

(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