rs12218564

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_022124.6(CDH23):c.4341T>C(p.Asp1447=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,613,346 control chromosomes in the GnomAD database, including 1,267 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 155 hom., cov: 33)

Exomes 𝑓: 0.010 ( 1112 hom. )

Consequence

CDH23
NM_022124.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.24

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 10-71738629-T-C is Benign according to our data. Variant chr10-71738629-T-C is described in ClinVar as [Benign]. Clinvar id is 45945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.24 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6 linkuse as main transcript	c.4341T>C	p.Asp1447=	synonymous_variant	35/70	ENST00000224721.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12 linkuse as main transcript	c.4341T>C	p.Asp1447=	synonymous_variant	35/70	5	NM_022124.6	P1	Q9H251-1
CDH23	ENST00000398792.3 linkuse as main transcript	n.1030T>C		non_coding_transcript_exon_variant	6/9	2

Frequencies

GnomAD3 genomes

AF:

0.0167

AC:

2537

AN:

152200

Hom.:

153

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00164

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0982

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.142

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.0113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000617

Gnomad OTH

AF:

0.0177

GnomAD3 exomes

AF:

0.0374

AC:

9300

AN:

248412

Hom.:

836

AF XY:

0.0298

AC XY:

4022

AN XY:

134874

show subpopulations

Gnomad AFR exome

AF:

0.00155

Gnomad AMR exome

AF:

0.178

Gnomad ASJ exome

AF:

0.00458

Gnomad EAS exome

AF:

0.144

Gnomad SAS exome

AF:

0.00199

Gnomad FIN exome

AF:

0.0102

Gnomad NFE exome

AF:

0.000631

Gnomad OTH exome

AF:

0.0274

GnomAD4 exome

AF:

0.00999

AC:

14596

AN:

1461028

Hom.:

1112

Cov.:

AF XY:

0.00890

AC XY:

6472

AN XY:

726792

show subpopulations

Gnomad4 AFR exome

AF:

0.00146

Gnomad4 AMR exome

AF:

0.169

Gnomad4 ASJ exome

AF:

0.00398

Gnomad4 EAS exome

AF:

0.126

Gnomad4 SAS exome

AF:

0.00240

Gnomad4 FIN exome

AF:

0.0108

Gnomad4 NFE exome

AF:

0.000264

Gnomad4 OTH exome

AF:

0.0130

GnomAD4 genome

AF:

0.0167

AC:

2547

AN:

152318

Hom.:

155

Cov.:

AF XY:

0.0191

AC XY:

1421

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00164

Gnomad4 AMR

AF:

0.0988

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.142

Gnomad4 SAS

AF:

0.00394

Gnomad4 FIN

AF:

0.0113

Gnomad4 NFE

AF:

0.000617

Gnomad4 OTH

AF:

0.0185

Alfa

AF:

0.00988

Hom.:

Bravo

AF:

0.0262

Asia WGS

AF:

0.0490

AC:

172

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000593

ClinVar

Significance: 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	Jun 12, 2009	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 05, 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. -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 08, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Usher syndrome type 1

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Usher syndrome type 1D

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Autosomal recessive nonsyndromic hearing loss 12

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

Cadd

Benign

0.63

Dann

Benign

0.66

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