rs111033289

Positions:

chr10-71800740-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_022124.6(CDH23):c.7467C>T(p.Arg2489=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00593 in 1,613,816 control chromosomes in the GnomAD database, including 213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 59 hom., cov: 32)

Exomes 𝑓: 0.0047 ( 154 hom. )

Consequence

CDH23
NM_022124.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.295

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.25).

BP6

Variant 10-71800740-C-T is Benign according to our data. Variant chr10-71800740-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 46031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71800740-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.295 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0821 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CDH23	NM_022124.6 linkuse as main transcript	c.7467C>T	p.Arg2489=	synonymous_variant	53/70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171933.1 linkuse as main transcript	c.747C>T	p.Arg249=	synonymous_variant	6/23		NP_001165404.1
CDH23	NM_001171934.1 linkuse as main transcript	c.747C>T	p.Arg249=	synonymous_variant	6/22		NP_001165405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 linkuse as main transcript	c.7467C>T	p.Arg2489=	synonymous_variant	53/70	5	NM_022124.6	ENSP00000224721	P1	Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.0177

AC:

2694

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0433

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0154

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.0894

Gnomad SAS

AF:

0.0104

Gnomad FIN

AF:

0.00462

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000985

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.0121

AC:

3016

AN:

249090

Hom.:

AF XY:

0.0106

AC XY:

1432

AN XY:

135138

show subpopulations

Gnomad AFR exome

AF:

0.0431

Gnomad AMR exome

AF:

0.0118

Gnomad ASJ exome

AF:

0.00418

Gnomad EAS exome

AF:

0.0848

Gnomad SAS exome

AF:

0.00465

Gnomad FIN exome

AF:

0.00311

Gnomad NFE exome

AF:

0.00104

Gnomad OTH exome

AF:

0.00843

GnomAD4 exome

AF:

0.00471

AC:

6877

AN:

1461606

Hom.:

154

Cov.:

AF XY:

0.00450

AC XY:

3271

AN XY:

727068

show subpopulations

Gnomad4 AFR exome

AF:

0.0431

Gnomad4 AMR exome

AF:

0.0134

Gnomad4 ASJ exome

AF:

0.00398

Gnomad4 EAS exome

AF:

0.0720

Gnomad4 SAS exome

AF:

0.00568

Gnomad4 FIN exome

AF:

0.00356

Gnomad4 NFE exome

AF:

0.000515

Gnomad4 OTH exome

AF:

0.0100

GnomAD4 genome

AF:

0.0177

AC:

2691

AN:

152210

Hom.:

Cov.:

AF XY:

0.0180

AC XY:

1338

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.0432

Gnomad4 AMR

AF:

0.0154

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.0888

Gnomad4 SAS

AF:

0.0104

Gnomad4 FIN

AF:

0.00462

Gnomad4 NFE

AF:

0.000985

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.00660

Hom.:

Bravo

AF:

0.0200

Asia WGS

AF:

0.0610

AC:

211

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.00107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 12, 2011	Arg2489Arg in exon 53 of CDH23: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located near a splice junction and is listed is dbSNP (rs111033289) with a frequency of 15% ( 18/120 chromosomes) in the East Asian population and 3.9% (49/1256 chromosomes) in the general population. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 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. -

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 12, 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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

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

BayesDel_noAF

Benign

-0.25

CADD

Benign

7.2

DANN

Benign

0.62

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