10-71675131-G-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_022124.6(CDH23):c.1469G>C(p.Gly490Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.175 in 1,613,382 control chromosomes in the GnomAD database, including 27,778 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 2218 hom., cov: 32)

Exomes 𝑓: 0.18 ( 25560 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 8.78

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 Benign. Variant got -18 ACMG points.

PM1

In a domain Cadherin 5 (size 100) in uniprot entity CAD23_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_022124.6

BP4

Computational evidence support a benign effect (MetaRNN=0.0017164052).

BP6

Variant 10-71675131-G-C is Benign according to our data. Variant chr10-71675131-G-C is described in ClinVar as [Benign]. Clinvar id is 45872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71675131-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6 link	c.1469G>C	p.Gly490Ala	missense_variant	Exon 15 of 70	ENST00000224721.12	NP_071407.4	Q9H251-1Q6P152
CDH23	NM_001171930.2 link	c.1469G>C	p.Gly490Ala	missense_variant	Exon 15 of 32		NP_001165401.1	Q9H251A0A087WYR8Q6P152
CDH23	NM_001171931.2 link	c.1469G>C	p.Gly490Ala	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.1469G>C	p.Gly490Ala	missense_variant	Exon 15 of 70	5	NM_022124.6	ENSP00000224721.9		Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.147

AC:

22325

AN:

152118

Hom.:

2215

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0332

Gnomad AMI

AF:

0.158

Gnomad AMR

AF:

0.135

Gnomad ASJ

AF:

0.184

Gnomad EAS

AF:

0.299

Gnomad SAS

AF:

0.296

Gnomad FIN

AF:

0.336

Gnomad MID

AF:

0.156

Gnomad NFE

AF:

0.165

Gnomad OTH

AF:

0.136

GnomAD3 exomes

AF:

0.200

AC:

49916

AN:

248990

Hom.:

5877

AF XY:

0.206

AC XY:

27845

AN XY:

135090

show subpopulations

Gnomad AFR exome

AF:

0.0299

Gnomad AMR exome

AF:

0.168

Gnomad ASJ exome

AF:

0.177

Gnomad EAS exome

AF:

0.303

Gnomad SAS exome

AF:

0.288

Gnomad FIN exome

AF:

0.331

Gnomad NFE exome

AF:

0.171

Gnomad OTH exome

AF:

0.195

GnomAD4 exome

AF:

0.178

AC:

260141

AN:

1461146

Hom.:

25560

Cov.:

AF XY:

0.182

AC XY:

132038

AN XY:

726832

show subpopulations

Gnomad4 AFR exome

AF:

0.0278

Gnomad4 AMR exome

AF:

0.165

Gnomad4 ASJ exome

AF:

0.181

Gnomad4 EAS exome

AF:

0.302

Gnomad4 SAS exome

AF:

0.286

Gnomad4 FIN exome

AF:

0.323

Gnomad4 NFE exome

AF:

0.164

Gnomad4 OTH exome

AF:

0.172

GnomAD4 genome

AF:

0.147

AC:

22342

AN:

152236

Hom.:

2218

Cov.:

AF XY:

0.158

AC XY:

11779

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.0332

Gnomad4 AMR

AF:

0.135

Gnomad4 ASJ

AF:

0.184

Gnomad4 EAS

AF:

0.299

Gnomad4 SAS

AF:

0.297

Gnomad4 FIN

AF:

0.336

Gnomad4 NFE

AF:

0.165

Gnomad4 OTH

AF:

0.142

Alfa

AF:

0.159

Hom.:

1674

Bravo

AF:

0.125

TwinsUK

AF:

0.174

AC:

644

ALSPAC

AF:

0.169

AC:

651

ESP6500AA

AF:

0.0354

AC:

149

ESP6500EA

AF:

0.164

AC:

1387

ExAC

AF:

0.199

AC:

24132

Asia WGS

AF:

0.308

AC:

1071

AN:

3476

EpiCase

AF:

0.165

EpiControl

AF:

0.164

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

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

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Jun 09, 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

- -

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 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. -

Autosomal recessive nonsyndromic hearing loss 12

Benign:2

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive nonsyndromic hearing loss 12;C1832845:Usher syndrome type 1D;C4539685:Pituitary adenoma 5, multiple types

Benign:1

Sep 01, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1

Benign:1

Feb 26, 2021

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Retinitis pigmentosa-deafness syndrome

Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;T;T;.;T;.

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D;D;D;D

MetaRNN

Benign

0.0017

T;T;T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.4

.;.;M;.;.;.

PrimateAI

Uncertain

0.65

REVEL

Uncertain

0.41

Sift4G

Uncertain

0.036

D;D;.;D;D;.

Polyphen

1.0

.;.;D;.;.;.

Vest4

0.70

ClinPred

0.011

GERP RS

5.7

Varity_R

0.60

gMVP

0.79

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