rs10999947

Positions:

chr10-71675149-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_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. 13/17 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

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=0.006324768).

BP6

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

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/exons	MANE	Protein
CDH23	NM_022124.6 linkuse as main transcript	c.1487G>A	p.Ser496Asn	missense_variant	15/70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171930.2 linkuse as main transcript	c.1487G>A	p.Ser496Asn	missense_variant	15/32		NP_001165401.1
CDH23	NM_001171931.2 linkuse as main transcript	c.1487G>A	p.Ser496Asn	missense_variant	15/26		NP_001165402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 linkuse as main transcript	c.1487G>A	p.Ser496Asn	missense_variant	15/70	5	NM_022124.6	ENSP00000224721	P1	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

GnomAD3 exomes

AF:

0.274

AC:

68122

AN:

249022

Hom.:

9483

AF XY:

0.272

AC XY:

36716

AN XY:

135132

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 SAS exome

AF:

0.270

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

Gnomad4 AFR exome

AF:

0.258

Gnomad4 AMR exome

AF:

0.304

Gnomad4 ASJ exome

AF:

0.186

Gnomad4 EAS exome

AF:

0.244

Gnomad4 SAS exome

AF:

0.272

Gnomad4 FIN exome

AF:

0.306

Gnomad4 NFE exome

AF:

0.272

Gnomad4 OTH exome

AF:

0.274

GnomAD4 genome

AF:

0.270

AC:

41072

AN:

152156

Hom.:

5568

Cov.:

AF XY:

0.272

AC XY:

20224

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.257

Gnomad4 AMR

AF:

0.296

Gnomad4 ASJ

AF:

0.187

Gnomad4 EAS

AF:

0.269

Gnomad4 SAS

AF:

0.260

Gnomad4 FIN

AF:

0.310

Gnomad4 NFE

AF:

0.271

Gnomad4 OTH

AF:

0.276

Alfa

AF:

0.266

Hom.:

13579

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
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	Jun 09, 2009	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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	- -
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. -

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

0.064

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.70

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;.;.;.

MutationTaster

Benign

1.0

P;P

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

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