rs11592462

Positions:

chr10-71790360-C-G

Variant summary

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

The NM_022124.6(CDH23):c.5996C>G(p.Thr1999Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 1,613,008 control chromosomes in the GnomAD database, including 179,488 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.41 ( 13508 hom., cov: 33)

Exomes 𝑓: 0.47 ( 165980 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 1.70

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=5.040169E-4).

BP6

Variant 10-71790360-C-G is Benign according to our data. Variant chr10-71790360-C-G is described in ClinVar as [Benign]. Clinvar id is 45997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71790360-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.495 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.5996C>G	p.Thr1999Ser	missense_variant	46/70	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.5996C>G	p.Thr1999Ser	missense_variant	46/70	5	NM_022124.6	ENSP00000224721.9		Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.409

AC:

62191

AN:

151952

Hom.:

13501

Cov.:

show subpopulations

Gnomad AFR

AF:

0.289

Gnomad AMI

AF:

0.395

Gnomad AMR

AF:

0.368

Gnomad ASJ

AF:

0.529

Gnomad EAS

AF:

0.165

Gnomad SAS

AF:

0.512

Gnomad FIN

AF:

0.427

Gnomad MID

AF:

0.516

Gnomad NFE

AF:

0.494

Gnomad OTH

AF:

0.430

GnomAD3 exomes

AF:

0.423

AC:

104457

AN:

246988

Hom.:

23611

AF XY:

0.439

AC XY:

58867

AN XY:

134186

show subpopulations

Gnomad AFR exome

AF:

0.279

Gnomad AMR exome

AF:

0.296

Gnomad ASJ exome

AF:

0.527

Gnomad EAS exome

AF:

0.165

Gnomad SAS exome

AF:

0.519

Gnomad FIN exome

AF:

0.422

Gnomad NFE exome

AF:

0.487

Gnomad OTH exome

AF:

0.445

GnomAD4 exome

AF:

0.470

AC:

687244

AN:

1460938

Hom.:

165980

Cov.:

AF XY:

0.473

AC XY:

344012

AN XY:

726756

show subpopulations

Gnomad4 AFR exome

AF:

0.276

Gnomad4 AMR exome

AF:

0.302

Gnomad4 ASJ exome

AF:

0.524

Gnomad4 EAS exome

AF:

0.141

Gnomad4 SAS exome

AF:

0.518

Gnomad4 FIN exome

AF:

0.428

Gnomad4 NFE exome

AF:

0.493

Gnomad4 OTH exome

AF:

0.456

GnomAD4 genome

AF:

0.409

AC:

62204

AN:

152070

Hom.:

13508

Cov.:

AF XY:

0.406

AC XY:

30193

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.288

Gnomad4 AMR

AF:

0.367

Gnomad4 ASJ

AF:

0.529

Gnomad4 EAS

AF:

0.165

Gnomad4 SAS

AF:

0.512

Gnomad4 FIN

AF:

0.427

Gnomad4 NFE

AF:

0.494

Gnomad4 OTH

AF:

0.434

Alfa

AF:

0.474

Hom.:

13287

Bravo

AF:

0.392

TwinsUK

AF:

0.485

AC:

1800

ALSPAC

AF:

0.495

AC:

1907

ESP6500AA

AF:

0.270

AC:

1130

ESP6500EA

AF:

0.486

AC:

4091

ExAC

AF:

0.426

AC:

51511

Asia WGS

AF:

0.331

AC:

1154

AN:

3478

EpiCase

AF:

0.500

EpiControl

AF:

0.499

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 28, 2013	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 31706157) -
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	- -

Usher syndrome type 1D

Benign:2

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

Autosomal recessive nonsyndromic hearing loss 12

Benign:2

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. -
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

0.088

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.67

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.0059

T;T

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.59

T;T

MetaRNN

Benign

0.00050

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.39

.;N

PrimateAI

Benign

0.41

REVEL

Benign

0.086

Sift4G

Benign

0.61

T;.

Polyphen

0.0

.;B

Vest4

0.16

MutPred

0.47

Gain of phosphorylation at Y1995 (P = 0.2156);Gain of phosphorylation at Y1995 (P = 0.2156);

ClinPred

0.014

GERP RS

4.1

Varity_R

0.099

gMVP

0.26

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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