10-71738598-G-A

Position:

chr10-71738598-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_022124.6(CDH23):c.4310G>A(p.Arg1437Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0305 in 1,613,762 control chromosomes in the GnomAD database, including 1,255 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.038 ( 159 hom., cov: 33)

Exomes 𝑓: 0.030 ( 1096 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13O:1

Conservation

PhyloP100: 1.45

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:

CDH23 (HGNC:):

CDH23 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017529726).

BP6

Variant 10-71738598-G-A is Benign according to our data. Variant chr10-71738598-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 45944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71738598-G-A is described in Lovd as [Benign]. Variant chr10-71738598-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0794 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6 linkuse as main transcript	c.4310G>A	p.Arg1437Gln	missense_variant	35/70	ENST00000224721.12	NP_071407.4	Q9H251-1Q6P152

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 linkuse as main transcript	c.4310G>A	p.Arg1437Gln	missense_variant	35/70	5	NM_022124.6	ENSP00000224721.9		Q9H251-1
CDH23	ENST00000398792.3 linkuse as main transcript	n.999G>A		non_coding_transcript_exon_variant	6/9	2

Frequencies

GnomAD3 genomes

AF:

0.0378

AC:

5753

AN:

152220

Hom.:

157

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0569

Gnomad AMI

AF:

0.0318

Gnomad AMR

AF:

0.0298

Gnomad ASJ

AF:

0.105

Gnomad EAS

AF:

0.0860

Gnomad SAS

AF:

0.0467

Gnomad FIN

AF:

0.00395

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0255

Gnomad OTH

AF:

0.0397

GnomAD3 exomes

AF:

0.0361

AC:

8985

AN:

249066

Hom.:

280

AF XY:

0.0375

AC XY:

5072

AN XY:

135170

show subpopulations

Gnomad AFR exome

AF:

0.0552

Gnomad AMR exome

AF:

0.0184

Gnomad ASJ exome

AF:

0.107

Gnomad EAS exome

AF:

0.0875

Gnomad SAS exome

AF:

0.0486

Gnomad FIN exome

AF:

0.00367

Gnomad NFE exome

AF:

0.0273

Gnomad OTH exome

AF:

0.0334

GnomAD4 exome

AF:

0.0297

AC:

43378

AN:

1461424

Hom.:

1096

Cov.:

AF XY:

0.0306

AC XY:

22270

AN XY:

726988

show subpopulations

Gnomad4 AFR exome

AF:

0.0540

Gnomad4 AMR exome

AF:

0.0193

Gnomad4 ASJ exome

AF:

0.108

Gnomad4 EAS exome

AF:

0.105

Gnomad4 SAS exome

AF:

0.0481

Gnomad4 FIN exome

AF:

0.00497

Gnomad4 NFE exome

AF:

0.0240

Gnomad4 OTH exome

AF:

0.0363

GnomAD4 genome

AF:

0.0379

AC:

5767

AN:

152338

Hom.:

159

Cov.:

AF XY:

0.0369

AC XY:

2751

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0572

Gnomad4 AMR

AF:

0.0297

Gnomad4 ASJ

AF:

0.105

Gnomad4 EAS

AF:

0.0860

Gnomad4 SAS

AF:

0.0468

Gnomad4 FIN

AF:

0.00395

Gnomad4 NFE

AF:

0.0255

Gnomad4 OTH

AF:

0.0393

Alfa

AF:

0.0324

Hom.:

147

Bravo

AF:

0.0418

TwinsUK

AF:

0.0248

AC:

ALSPAC

AF:

0.0252

AC:

ESP6500AA

AF:

0.0487

AC:

203

ESP6500EA

AF:

0.0287

AC:

243

ExAC

AF:

0.0371

AC:

4488

Asia WGS

AF:

0.0630

AC:

220

AN:

3478

EpiCase

AF:

0.0333

EpiControl

AF:

0.0354

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4Other:1

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 16, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 12, 2009	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2013	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Usher syndrome type 1D

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, 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 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

Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

Usher syndrome type 1

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0079

T;T

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.62

T;T

MetaRNN

Benign

0.0018

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.76

.;N

PrimateAI

Benign

0.24

REVEL

Benign

0.017

Sift4G

Uncertain

0.019

D;.

Polyphen

0.13

.;B

Vest4

0.31

ClinPred

0.0097

GERP RS

1.5

Varity_R

0.24

gMVP

0.41

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