rs1227051

Variant summary

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

The NM_022124.6(CDH23):c.4723G>A(p.Ala1575Thr) variant causes a missense change. The variant allele was found at a frequency of 0.771 in 1,611,736 control chromosomes in the GnomAD database, including 481,005 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1575A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.73 ( 41484 hom., cov: 33)

Exomes 𝑓: 0.78 ( 439521 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 6.19

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=8.691493E-6).

BP6

Variant 10-71741799-G-A is Benign according to our data. Variant chr10-71741799-G-A is described in ClinVar as [Benign]. Clinvar id is 45955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71741799-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.8 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.4723G>A	p.Ala1575Thr	missense_variant	38/70	ENST00000224721.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12 linkuse as main transcript	c.4723G>A	p.Ala1575Thr	missense_variant	38/70	5	NM_022124.6	P1	Q9H251-1
CDH23	ENST00000398792.3 linkuse as main transcript	n.1412G>A		non_coding_transcript_exon_variant	9/9	2

Frequencies

GnomAD3 genomes

AF:

0.734

AC:

111674

AN:

152044

Hom.:

41460

Cov.:

show subpopulations

Gnomad AFR

AF:

0.611

Gnomad AMI

AF:

0.745

Gnomad AMR

AF:

0.769

Gnomad ASJ

AF:

0.859

Gnomad EAS

AF:

0.822

Gnomad SAS

AF:

0.786

Gnomad FIN

AF:

0.747

Gnomad MID

AF:

0.734

Gnomad NFE

AF:

0.782

Gnomad OTH

AF:

0.761

GnomAD3 exomes

AF:

0.774

AC:

189554

AN:

244850

Hom.:

73661

AF XY:

0.777

AC XY:

103420

AN XY:

133082

show subpopulations

Gnomad AFR exome

AF:

0.603

Gnomad AMR exome

AF:

0.776

Gnomad ASJ exome

AF:

0.850

Gnomad EAS exome

AF:

0.832

Gnomad SAS exome

AF:

0.786

Gnomad FIN exome

AF:

0.746

Gnomad NFE exome

AF:

0.782

Gnomad OTH exome

AF:

0.789

GnomAD4 exome

AF:

0.775

AC:

1131293

AN:

1459574

Hom.:

439521

Cov.:

AF XY:

0.776

AC XY:

563594

AN XY:

725860

show subpopulations

Gnomad4 AFR exome

AF:

0.595

Gnomad4 AMR exome

AF:

0.770

Gnomad4 ASJ exome

AF:

0.853

Gnomad4 EAS exome

AF:

0.824

Gnomad4 SAS exome

AF:

0.785

Gnomad4 FIN exome

AF:

0.747

Gnomad4 NFE exome

AF:

0.778

Gnomad4 OTH exome

AF:

0.771

GnomAD4 genome

AF:

0.734

AC:

111743

AN:

152162

Hom.:

41484

Cov.:

AF XY:

0.734

AC XY:

54617

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.611

Gnomad4 AMR

AF:

0.769

Gnomad4 ASJ

AF:

0.859

Gnomad4 EAS

AF:

0.821

Gnomad4 SAS

AF:

0.788

Gnomad4 FIN

AF:

0.747

Gnomad4 NFE

AF:

0.782

Gnomad4 OTH

AF:

0.763

Alfa

AF:

0.782

Hom.:

116721

Bravo

AF:

0.734

TwinsUK

AF:

0.785

AC:

2909

ALSPAC

AF:

0.779

AC:

3004

ESP6500AA

AF:

0.634

AC:

2783

ESP6500EA

AF:

0.796

AC:

6814

ExAC

AF:

0.767

AC:

92912

Asia WGS

AF:

0.780

AC:

2712

AN:

3478

EpiCase

AF:

0.794

EpiControl

AF:

0.790

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 02, 2012	Inferred frequency = 172/301 -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Usher syndrome type 1D

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Autosomal recessive nonsyndromic hearing loss 12

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
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. -

Usher syndrome type 1

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Retinitis pigmentosa-deafness syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.57

Cadd

Benign

Dann

Benign

0.75

DEOGEN2

Benign

0.0049

T;T

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.14

T;T

MetaRNN

Benign

0.0000087

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.42

Sift4G

Benign

1.0

T;.

Vest4

0.082

ClinPred

0.0096

GERP RS

5.1

Varity_R

0.17

gMVP

0.12

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