rs74145660

Positions:

Variant summary

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

The NM_022124.6(CDH23):c.5418C>G(p.Asp1806Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00949 in 1,613,886 control chromosomes in the GnomAD database, including 260 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 43 hom., cov: 33)

Exomes 𝑓: 0.0090 ( 217 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.83

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017141998).

BP6

Variant 10-71784336-C-G is Benign according to our data. Variant chr10-71784336-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 45976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71784336-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0758 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.5418C>G	p.Asp1806Glu	missense_variant	42/70	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.5418C>G	p.Asp1806Glu	missense_variant	42/70	5	NM_022124.6	ENSP00000224721	P1	Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.0144

AC:

2185

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0258

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.00818

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.0826

Gnomad SAS

AF:

0.00993

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00645

Gnomad OTH

AF:

0.0148

GnomAD3 exomes

AF:

0.0140

AC:

3494

AN:

249132

Hom.:

AF XY:

0.0135

AC XY:

1831

AN XY:

135166

show subpopulations

Gnomad AFR exome

AF:

0.0260

Gnomad AMR exome

AF:

0.00739

Gnomad ASJ exome

AF:

0.00856

Gnomad EAS exome

AF:

0.0918

Gnomad SAS exome

AF:

0.00886

Gnomad FIN exome

AF:

0.000928

Gnomad NFE exome

AF:

0.00648

Gnomad OTH exome

AF:

0.0131

GnomAD4 exome

AF:

0.00899

AC:

13137

AN:

1461582

Hom.:

217

Cov.:

AF XY:

0.00902

AC XY:

6561

AN XY:

727094

show subpopulations

Gnomad4 AFR exome

AF:

0.0276

Gnomad4 AMR exome

AF:

0.00763

Gnomad4 ASJ exome

AF:

0.00934

Gnomad4 EAS exome

AF:

0.0886

Gnomad4 SAS exome

AF:

0.00896

Gnomad4 FIN exome

AF:

0.000749

Gnomad4 NFE exome

AF:

0.00585

Gnomad4 OTH exome

AF:

0.0111

GnomAD4 genome

AF:

0.0143

AC:

2185

AN:

152304

Hom.:

Cov.:

AF XY:

0.0147

AC XY:

1094

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0258

Gnomad4 AMR

AF:

0.00817

Gnomad4 ASJ

AF:

0.00576

Gnomad4 EAS

AF:

0.0822

Gnomad4 SAS

AF:

0.00993

Gnomad4 FIN

AF:

0.000659

Gnomad4 NFE

AF:

0.00645

Gnomad4 OTH

AF:

0.0151

Alfa

AF:

0.00882

Hom.:

Bravo

AF:

0.0166

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00623

AC:

ESP6500AA

AF:

0.0240

AC:

ESP6500EA

AF:

0.00758

AC:

ExAC

AF:

0.0144

AC:

1742

EpiCase

AF:

0.00753

EpiControl

AF:

0.00949

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 20, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 22, 2012	Asp1806Glu in exon 42 of CDH23: This variant is not expected to have clinical si gnificance due to its occurrence at an equal frequency in cases compared to the general population (Roux 2006, Wagatsuma 2007) and is listed in dbSNP with 10/28 8 (3.5%) frequency (rs74145660). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 13, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	literature only	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 26, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Usher syndrome type 1D

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

Autosomal recessive nonsyndromic hearing loss 12;C1832845:Usher syndrome type 1D;C4539685:Pituitary adenoma 5, multiple types

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 12, 2022

- -

Usher syndrome type 1

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Autosomal recessive nonsyndromic hearing loss 12

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.31

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0056

T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.72

T;T

MetaRNN

Benign

0.0017

T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.66

.;N

MutationTaster

Benign

0.90

PrimateAI

Uncertain

0.49

REVEL

Benign

0.15

Sift4G

Uncertain

0.028

D;.

Polyphen

1.0

.;D

Vest4

0.20

MutPred

0.40

Loss of ubiquitination at K1805 (P = 0.0715);Loss of ubiquitination at K1805 (P = 0.0715);

ClinPred

0.066

GERP RS

-5.3

Varity_R

0.082

gMVP

0.36

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