rs41281330

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_022124.6(CDH23):c.4858G>A(p.Val1620Met) variant causes a missense change. The variant allele was found at a frequency of 0.0144 in 1,611,636 control chromosomes in the GnomAD database, including 365 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1620G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.011 ( 24 hom., cov: 32)

Exomes 𝑓: 0.015 ( 341 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 5.23

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=0.0050043464).

BP6

Variant 10-71777692-G-A is Benign according to our data. Variant chr10-71777692-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 45957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71777692-G-A is described in Lovd as [Benign]. Variant chr10-71777692-G-A is described in Lovd as [Likely_benign]. Variant chr10-71777692-G-A is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0115 (1747/152256) while in subpopulation SAS AF= 0.0451 (218/4832). AF 95% confidence interval is 0.0402. There are 24 homozygotes in gnomad4. There are 895 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 24 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6 linkuse as main transcript	c.4858G>A	p.Val1620Met	missense_variant	39/70	ENST00000224721.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12 linkuse as main transcript	c.4858G>A	p.Val1620Met	missense_variant	39/70	5	NM_022124.6	P1	Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.0115

AC:

1744

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00229

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00753

Gnomad ASJ

AF:

0.0683

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0445

Gnomad FIN

AF:

0.0118

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0135

Gnomad OTH

AF:

0.0153

GnomAD3 exomes

AF:

0.0174

AC:

4236

AN:

243606

Hom.:

AF XY:

0.0195

AC XY:

2582

AN XY:

132466

show subpopulations

Gnomad AFR exome

AF:

0.00204

Gnomad AMR exome

AF:

0.00792

Gnomad ASJ exome

AF:

0.0672

Gnomad EAS exome

AF:

0.000281

Gnomad SAS exome

AF:

0.0487

Gnomad FIN exome

AF:

0.0116

Gnomad NFE exome

AF:

0.0130

Gnomad OTH exome

AF:

0.0214

GnomAD4 exome

AF:

0.0148

AC:

21534

AN:

1459380

Hom.:

341

Cov.:

AF XY:

0.0160

AC XY:

11631

AN XY:

725712

show subpopulations

Gnomad4 AFR exome

AF:

0.00191

Gnomad4 AMR exome

AF:

0.00818

Gnomad4 ASJ exome

AF:

0.0701

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0484

Gnomad4 FIN exome

AF:

0.0111

Gnomad4 NFE exome

AF:

0.0119

Gnomad4 OTH exome

AF:

0.0195

GnomAD4 genome

AF:

0.0115

AC:

1747

AN:

152256

Hom.:

Cov.:

AF XY:

0.0120

AC XY:

895

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.00229

Gnomad4 AMR

AF:

0.00752

Gnomad4 ASJ

AF:

0.0683

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.0451

Gnomad4 FIN

AF:

0.0118

Gnomad4 NFE

AF:

0.0135

Gnomad4 OTH

AF:

0.0151

Alfa

AF:

0.0154

Hom.:

Bravo

AF:

0.00987

TwinsUK

AF:

0.0138

AC:

ALSPAC

AF:

0.0132

AC:

ESP6500AA

AF:

0.00191

AC:

ESP6500EA

AF:

0.0150

AC:

126

ExAC

AF:

0.0171

AC:

2071

Asia WGS

AF:

0.0100

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 27, 2010	Val1620Met in exon 39 of CDH23: This variant is not expected to have clinical si gnificance due to its occurrence at a similar frequency in the general populatio n and it has been reported as presumed non-pathogenic (Astuto 2002, Oshima 2008, Ouyang 2005). In addition, this variant is listed in dbSNP (rs41281330 - no fre quency data). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 20, 2013	- -

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 02, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 19, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 23591405, 27884173, 30245029) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CDH23: BS1, BS2 -

Usher syndrome type 1D

Benign:2

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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

Autosomal recessive nonsyndromic hearing loss 12

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

May 04, 2022

- -

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

Uncertain

0.42

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.34

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.14

T;T

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

D;D

MetaRNN

Benign

0.0050

T;T

MetaSVM

Uncertain

0.085

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.64

Sift4G

Uncertain

0.0020

D;.

Polyphen

1.0

.;D

Vest4

0.45

ClinPred

0.012

GERP RS

5.9

Varity_R

0.12

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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