rs1227065

Positions:

Variant summary

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

The NM_022124.6(CDH23):c.4051A>G(p.Asn1351Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.807 in 1,599,966 control chromosomes in the GnomAD database, including 521,105 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.80 ( 48634 hom., cov: 33)

Exomes 𝑓: 0.81 ( 472471 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 7.75

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:

C10orf105 (HGNC:20304): (chromosome 10 open reading frame 105) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

C10orf105 links:

CDH23 (HGNC:):

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=1.1604471E-6).

BP6

Variant 10-71732322-A-G is Benign according to our data. Variant chr10-71732322-A-G is described in ClinVar as [Benign]. Clinvar id is 45937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71732322-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.811 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6 linkuse as main transcript	c.4051A>G	p.Asn1351Asp	missense_variant	32/70	ENST00000224721.12	NP_071407.4	Q9H251-1Q6P152
CDH23	NM_001171930.2 linkuse as main transcript	c.4051A>G	p.Asn1351Asp	missense_variant	32/32		NP_001165401.1	Q9H251A0A087WYR8Q6P152
C10orf105	NM_001168390.2 linkuse as main transcript	c.-6+5406T>C		intron_variant			NP_001161862.1	Q8TEF2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 linkuse as main transcript	c.4051A>G	p.Asn1351Asp	missense_variant	32/70	5	NM_022124.6	ENSP00000224721.9		Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.800

AC:

121582

AN:

152062

Hom.:

48603

Cov.:

show subpopulations

Gnomad AFR

AF:

0.777

Gnomad AMI

AF:

0.813

Gnomad AMR

AF:

0.799

Gnomad ASJ

AF:

0.864

Gnomad EAS

AF:

0.832

Gnomad SAS

AF:

0.800

Gnomad FIN

AF:

0.754

Gnomad MID

AF:

0.766

Gnomad NFE

AF:

0.815

Gnomad OTH

AF:

0.805

GnomAD3 exomes

AF:

0.807

AC:

183095

AN:

226914

Hom.:

73864

AF XY:

0.808

AC XY:

99338

AN XY:

122906

show subpopulations

Gnomad AFR exome

AF:

0.767

Gnomad AMR exome

AF:

0.794

Gnomad ASJ exome

AF:

0.856

Gnomad EAS exome

AF:

0.846

Gnomad SAS exome

AF:

0.800

Gnomad FIN exome

AF:

0.756

Gnomad NFE exome

AF:

0.817

Gnomad OTH exome

AF:

0.816

GnomAD4 exome

AF:

0.808

AC:

1169142

AN:

1447786

Hom.:

472471

Cov.:

AF XY:

0.808

AC XY:

580806

AN XY:

718984

show subpopulations

Gnomad4 AFR exome

AF:

0.763

Gnomad4 AMR exome

AF:

0.789

Gnomad4 ASJ exome

AF:

0.858

Gnomad4 EAS exome

AF:

0.831

Gnomad4 SAS exome

AF:

0.800

Gnomad4 FIN exome

AF:

0.757

Gnomad4 NFE exome

AF:

0.811

Gnomad4 OTH exome

AF:

0.807

GnomAD4 genome

AF:

0.799

AC:

121662

AN:

152180

Hom.:

48634

Cov.:

AF XY:

0.797

AC XY:

59265

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.776

Gnomad4 AMR

AF:

0.799

Gnomad4 ASJ

AF:

0.864

Gnomad4 EAS

AF:

0.832

Gnomad4 SAS

AF:

0.801

Gnomad4 FIN

AF:

0.754

Gnomad4 NFE

AF:

0.815

Gnomad4 OTH

AF:

0.807

Alfa

AF:

0.817

Hom.:

131434

Bravo

AF:

0.803

TwinsUK

AF:

0.816

AC:

3027

ALSPAC

AF:

0.812

AC:

3128

ESP6500AA

AF:

0.791

AC:

3275

ESP6500EA

AF:

0.824

AC:

6922

ExAC

AF:

0.794

AC:

95662

Asia WGS

AF:

0.798

AC:

2775

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 02, 2012	Inferred frequency = 196/301 -
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	Eurofins Ntd Llc (ga)	Sep 20, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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. -

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

0.052

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.52

DEOGEN2

Benign

0.0038

T;T;T;T

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.22

T;T;T;T

MetaRNN

Benign

0.0000012

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.61

.;.;N;.

PrimateAI

Uncertain

0.52

REVEL

Benign

0.15

Sift4G

Benign

1.0

T;T;.;T

Vest4

0.20

ClinPred

0.022

GERP RS

5.0

Varity_R

0.42

gMVP

0.22

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