rs140884994

Positions:

chr10-71812781-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_022124.6(CDH23):c.9524G>A(p.Arg3175His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000225 in 1,613,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3175C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: 9.71

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:

LOC124902446 (HGNC:):

LOC124902446 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.30039865).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6 linkuse as main transcript	c.9524G>A	p.Arg3175His	missense_variant	68/70	ENST00000224721.12
LOC124902446	XR_007062185.1 linkuse as main transcript			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12 linkuse as main transcript	c.9524G>A	p.Arg3175His	missense_variant	68/70	5	NM_022124.6	P1	Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.000269

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000279

AC:

AN:

246978

Hom.:

AF XY:

0.000321

AC XY:

AN XY:

134030

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000876

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000561

Gnomad FIN exome

AF:

0.000420

Gnomad NFE exome

AF:

0.000322

Gnomad OTH exome

AF:

0.000667

GnomAD4 exome

AF:

0.000220

AC:

322

AN:

1460780

Hom.:

Cov.:

AF XY:

0.000231

AC XY:

168

AN XY:

726576

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000135

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000511

Gnomad4 FIN exome

AF:

0.000581

Gnomad4 NFE exome

AF:

0.000196

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.000269

AC:

AN:

152354

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00103

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000255

Hom.:

Bravo

AF:

0.000253

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000240

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.000273

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 19, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	CDH23: PM2, PP3 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 29, 2021

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 25, 2023

Variant summary: CDH23 c.9524G>A (p.Arg3175His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 246978 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CDH23 causing Usher Syndrome (0.00028 vs 0.0032), allowing no conclusion about variant significance. c.9524G>A has been reported in the literature in individuals affected with Usher Syndrome or non-syndromic hearing loss (e.g. Astuto_2002, Usami_2008, Cabanillas_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Usher Syndrome. At least two publications report experimental evidence evaluating an impact on protein function (e.g. Yonezawa_2006, Takahashi_2016), suggesting that the variant does not alter protein localization but may impact microtubule formation. However, these findings do not allow convincing conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 12075507, 29986705, 27349180, 18368581, 16281288). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=5) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 11, 2017

- -

Pituitary adenoma 5, multiple types

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 02, 2022

- -

Usher syndrome type 1

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Autosomal recessive nonsyndromic hearing loss 12

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

May 03, 2019

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.025

T;T;.;.

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.30

T;T;T;T

MetaSVM

Uncertain

0.36

MutationAssessor

Benign

1.0

.;L;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.77

.;.;.;N

REVEL

Pathogenic

0.71

Sift

Pathogenic

0.0

.;.;.;D

Sift4G

Pathogenic

0.0

D;.;D;D

Polyphen

1.0

.;D;.;.

Vest4

0.78

MVP

0.94

MPC

0.45

ClinPred

0.17

GERP RS

5.4

Varity_R

0.43

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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