rs2290021

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_022124.6(CDH23):c.9873G>A(p.Thr3291Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0967 in 1,610,376 control chromosomes in the GnomAD database, including 9,966 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.092 ( 896 hom., cov: 34)

Exomes 𝑓: 0.097 ( 9070 hom. )

Consequence

CDH23
NM_022124.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: -3.53

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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 10-71815086-G-A is Benign according to our data. Variant chr10-71815086-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.53 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.273 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6 link	c.9873G>A	p.Thr3291Thr	synonymous_variant	Exon 70 of 70	ENST00000224721.12	NP_071407.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 link	c.9873G>A	p.Thr3291Thr	synonymous_variant	Exon 70 of 70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes

AF:

0.0917

AC:

13958

AN:

152210

Hom.:

894

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0490

Gnomad AMI

AF:

0.116

Gnomad AMR

AF:

0.171

Gnomad ASJ

AF:

0.0570

Gnomad EAS

AF:

0.285

Gnomad SAS

AF:

0.118

Gnomad FIN

AF:

0.127

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0800

Gnomad OTH

AF:

0.0812

GnomAD2 exomes

AF:

0.132

AC:

31820

AN:

240552

AF XY:

0.122

show subpopulations

Gnomad AFR exome

AF:

0.0478

Gnomad AMR exome

AF:

0.308

Gnomad ASJ exome

AF:

0.0573

Gnomad EAS exome

AF:

0.295

Gnomad FIN exome

AF:

0.130

Gnomad NFE exome

AF:

0.0780

Gnomad OTH exome

AF:

0.116

GnomAD4 exome

AF:

0.0973

AC:

141839

AN:

1458048

Hom.:

9070

Cov.:

AF XY:

0.0957

AC XY:

69422

AN XY:

725224

show subpopulations

African (AFR)

AF:

0.0448

AC:

1498

AN:

33440

American (AMR)

AF:

0.293

AC:

12942

AN:

44144

Ashkenazi Jewish (ASJ)

AF:

0.0576

AC:

1499

AN:

26036

East Asian (EAS)

AF:

0.301

AC:

11900

AN:

39584

South Asian (SAS)

AF:

0.104

AC:

8887

AN:

85864

European-Finnish (FIN)

AF:

0.129

AC:

6713

AN:

52172

Middle Eastern (MID)

AF:

0.0326

AC:

188

AN:

5764

European-Non Finnish (NFE)

AF:

0.0829

AC:

92082

AN:

1110810

Other (OTH)

AF:

0.102

AC:

6130

AN:

60234

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

8146

16293

24439

32586

40732

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3788

7576

11364

15152

18940

<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:

0.0917

AC:

13962

AN:

152328

Hom.:

896

Cov.:

AF XY:

0.0960

AC XY:

7151

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.0489

AC:

2034

AN:

41580

American (AMR)

AF:

0.171

AC:

2618

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.0570

AC:

198

AN:

3472

East Asian (EAS)

AF:

0.285

AC:

1476

AN:

5182

South Asian (SAS)

AF:

0.117

AC:

567

AN:

4828

European-Finnish (FIN)

AF:

0.127

AC:

1345

AN:

10626

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0800

AC:

5439

AN:

68010

Other (OTH)

AF:

0.0808

AC:

171

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

649

1299

1948

2598

3247

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

162

324

486

648

810

<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:

0.0861

Hom.:

454

Bravo

AF:

0.0988

Asia WGS

AF:

0.201

AC:

696

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Jun 12, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 05, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Aug 11, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome type 1D

Benign:2

Jan 13, 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. -

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 12

Benign:2

Jan 13, 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

- -

Atypical Gaucher Disease

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Combined PSAP deficiency

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

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

- -

Galactosylceramide beta-galactosidase deficiency

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hearing loss, autosomal recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinitis pigmentosa-deafness syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Metachromatic leukodystrophy

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.22

(source)

DANN

Benign

0.90

PhyloP100

-3.5

Mutation Taster

=85/15

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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