rs10466026

Positions:

Variant summary

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

The NM_022124.6(CDH23):c.6130G>A(p.Glu2044Lys) variant causes a missense change. The variant allele was found at a frequency of 0.289 in 1,612,844 control chromosomes in the GnomAD database, including 70,502 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.29 ( 6533 hom., cov: 32)

Exomes 𝑓: 0.29 ( 63969 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 3.85

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 19 (size 109) in uniprot entity CAD23_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_022124.6

BP4

Computational evidence support a benign effect (MetaRNN=0.0011279583).

BP6

Variant 10-71791212-G-A is Benign according to our data. Variant chr10-71791212-G-A is described in ClinVar as [Benign]. Clinvar id is 46002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71791212-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.517 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.6130G>A	p.Glu2044Lys	missense_variant	47/70	ENST00000224721.12	NP_071407.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 linkuse as main transcript	c.6130G>A	p.Glu2044Lys	missense_variant	47/70	5	NM_022124.6	ENSP00000224721	P1	Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.286

AC:

43472

AN:

152008

Hom.:

6526

Cov.:

show subpopulations

Gnomad AFR

AF:

0.265

Gnomad AMI

AF:

0.383

Gnomad AMR

AF:

0.332

Gnomad ASJ

AF:

0.213

Gnomad EAS

AF:

0.533

Gnomad SAS

AF:

0.243

Gnomad FIN

AF:

0.348

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.266

Gnomad OTH

AF:

0.269

GnomAD3 exomes

AF:

0.309

AC:

76554

AN:

247484

Hom.:

12819

AF XY:

0.297

AC XY:

39847

AN XY:

134222

show subpopulations

Gnomad AFR exome

AF:

0.264

Gnomad AMR exome

AF:

0.428

Gnomad ASJ exome

AF:

0.210

Gnomad EAS exome

AF:

0.529

Gnomad SAS exome

AF:

0.229

Gnomad FIN exome

AF:

0.349

Gnomad NFE exome

AF:

0.269

Gnomad OTH exome

AF:

0.280

GnomAD4 exome

AF:

0.289

AC:

421828

AN:

1460718

Hom.:

63969

Cov.:

AF XY:

0.284

AC XY:

206636

AN XY:

726558

show subpopulations

Gnomad4 AFR exome

AF:

0.268

Gnomad4 AMR exome

AF:

0.418

Gnomad4 ASJ exome

AF:

0.212

Gnomad4 EAS exome

AF:

0.575

Gnomad4 SAS exome

AF:

0.227

Gnomad4 FIN exome

AF:

0.347

Gnomad4 NFE exome

AF:

0.279

Gnomad4 OTH exome

AF:

0.288

GnomAD4 genome

AF:

0.286

AC:

43495

AN:

152126

Hom.:

6533

Cov.:

AF XY:

0.290

AC XY:

21542

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.265

Gnomad4 AMR

AF:

0.332

Gnomad4 ASJ

AF:

0.213

Gnomad4 EAS

AF:

0.534

Gnomad4 SAS

AF:

0.243

Gnomad4 FIN

AF:

0.348

Gnomad4 NFE

AF:

0.266

Gnomad4 OTH

AF:

0.266

Alfa

AF:

0.267

Hom.:

9293

Bravo

AF:

0.290

TwinsUK

AF:

0.290

AC:

1076

ALSPAC

AF:

0.280

AC:

1079

ESP6500AA

AF:

0.270

AC:

1189

ESP6500EA

AF:

0.263

AC:

2258

ExAC

AF:

0.300

AC:

36393

Asia WGS

AF:

0.348

AC:

1212

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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	Jan 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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 30, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Autosomal recessive nonsyndromic hearing loss 12

Benign:2

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. -
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

- -

Retinitis pigmentosa-deafness syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.014

T;T

Eigen

Benign

-0.072

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.69

T;T

MetaRNN

Benign

0.0011

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.72

.;N

MutationTaster

Benign

0.027

PrimateAI

Uncertain

0.51

REVEL

Benign

0.18

Sift4G

Uncertain

0.041

D;.

Polyphen

0.64

.;P

Vest4

0.48

ClinPred

0.022

GERP RS

5.9

Varity_R

0.13

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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