rs62622410

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_022124.6(CDH23):c.1423G>A(p.Val475Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00223 in 1,613,968 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 39 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 33 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.52

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=0.010747403).

BP6

Variant 10-71646591-G-A is Benign according to our data. Variant chr10-71646591-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 45867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71646591-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0118 (1795/152260) while in subpopulation AFR AF= 0.0407 (1690/41528). AF 95% confidence interval is 0.0391. There are 39 homozygotes in gnomad4. There are 805 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 39 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CDH23	NM_022124.6 linkuse as main transcript	c.1423G>A	p.Val475Met	missense_variant	14/70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171930.2 linkuse as main transcript	c.1423G>A	p.Val475Met	missense_variant	14/32		NP_001165401.1
CDH23	NM_001171931.2 linkuse as main transcript	c.1423G>A	p.Val475Met	missense_variant	14/26		NP_001165402.1
CDH23	NM_052836.4 linkuse as main transcript	c.1423G>A	p.Val475Met	missense_variant	14/14		NP_443068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 linkuse as main transcript	c.1423G>A	p.Val475Met	missense_variant	14/70	5	NM_022124.6	ENSP00000224721	P1	Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.0118

AC:

1793

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0408

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00471

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00956

GnomAD3 exomes

AF:

0.00321

AC:

801

AN:

249272

Hom.:

AF XY:

0.00241

AC XY:

326

AN XY:

135240

show subpopulations

Gnomad AFR exome

AF:

0.0433

Gnomad AMR exome

AF:

0.00269

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000168

Gnomad OTH exome

AF:

0.00182

GnomAD4 exome

AF:

0.00124

AC:

1810

AN:

1461708

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

769

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.0395

Gnomad4 AMR exome

AF:

0.00266

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000123

Gnomad4 OTH exome

AF:

0.00330

GnomAD4 genome

AF:

0.0118

AC:

1795

AN:

152260

Hom.:

Cov.:

AF XY:

0.0108

AC XY:

805

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0407

Gnomad4 AMR

AF:

0.00471

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00946

Alfa

AF:

0.00164

Hom.:

Bravo

AF:

0.0135

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0405

AC:

173

ESP6500EA

AF:

0.000471

AC:

ExAC

AF:

0.00383

AC:

464

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 08, 2013	Val475Met in Exon 14A of CDH23: This variant is not expected to have clinical si gnificance because it has been identified in 4.1% (173/4270) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs62622410). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 05, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 17, 2022	Variant summary: CDH23 c.1423G>A (p.Val475Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0032 in 249272 control chromosomes, predominantly at a frequency of 0.043 within the African or African-American subpopulation in the gnomAD database, including 17 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH23 causing Usher Syndrome phenotype (0.0032), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as benign (n=4) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 10, 2018	This variant is associated with the following publications: (PMID: 25262649, 22952768, 30245029) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Usher syndrome type 1D

Benign:1

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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Usher syndrome type 1

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 12, 2019

- -

Autosomal recessive nonsyndromic hearing loss 12

Benign:1

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.050

T;T;T;.;.;.;T;.;.

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.88

D;D;D;D;D;D;D;D;D

MetaRNN

Benign

0.011

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.46

MutationAssessor

Uncertain

2.3

.;.;M;M;.;.;.;.;.

MutationTaster

Benign

0.80

D;D;D;D

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.1

N;.;.;.;.;.;.;.;.

REVEL

Benign

0.28

Sift

Benign

0.056

T;.;.;.;.;.;.;.;.

Sift4G

Benign

0.22

T;D;.;T;T;T;T;.;.

Polyphen

1.0, 0.79

.;.;D;P;.;.;.;.;.

Vest4

0.45

MVP

0.75

ClinPred

0.012

GERP RS

4.8

Varity_R

0.19

gMVP

0.34

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