rs41281338

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_022124.6(CDH23):c.7762G>C(p.Glu2588Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00972 in 1,591,622 control chromosomes in the GnomAD database, including 124 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0073 ( 7 hom., cov: 31)

Exomes 𝑓: 0.010 ( 117 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: -0.00300

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0042585135).

BP6

Variant 10-71803310-G-C is Benign according to our data. Variant chr10-71803310-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46038.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3, Benign=4}. Variant chr10-71803310-G-C is described in Lovd as [Benign]. Variant chr10-71803310-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00726 (1105/152290) while in subpopulation SAS AF= 0.0207 (100/4822). AF 95% confidence interval is 0.0174. There are 7 homozygotes in gnomad4. There are 546 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6 link	c.7762G>C	p.Glu2588Gln	missense_variant	55/70	ENST00000224721.12	NP_071407.4	Q9H251-1Q6P152
CDH23	NM_001171933.1 link	c.1042G>C	p.Glu348Gln	missense_variant	8/23		NP_001165404.1	Q9H251-7
CDH23	NM_001171934.1 link	c.1042G>C	p.Glu348Gln	missense_variant	8/22		NP_001165405.1	Q9H251-9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 link	c.7762G>C	p.Glu2588Gln	missense_variant	55/70	5	NM_022124.6	ENSP00000224721.9		Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.00727

AC:

1107

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00159

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00608

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0209

Gnomad FIN

AF:

0.00320

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0113

Gnomad OTH

AF:

0.00716

GnomAD3 exomes

AF:

0.00907

AC:

1900

AN:

209470

Hom.:

AF XY:

0.0102

AC XY:

1157

AN XY:

113284

show subpopulations

Gnomad AFR exome

AF:

0.00152

Gnomad AMR exome

AF:

0.00362

Gnomad ASJ exome

AF:

0.00538

Gnomad EAS exome

AF:

0.000199

Gnomad SAS exome

AF:

0.0237

Gnomad FIN exome

AF:

0.00374

Gnomad NFE exome

AF:

0.0106

Gnomad OTH exome

AF:

0.00878

GnomAD4 exome

AF:

0.00998

AC:

14361

AN:

1439332

Hom.:

117

Cov.:

AF XY:

0.0105

AC XY:

7470

AN XY:

713934

show subpopulations

Gnomad4 AFR exome

AF:

0.00131

Gnomad4 AMR exome

AF:

0.00363

Gnomad4 ASJ exome

AF:

0.00565

Gnomad4 EAS exome

AF:

0.0000524

Gnomad4 SAS exome

AF:

0.0237

Gnomad4 FIN exome

AF:

0.00420

Gnomad4 NFE exome

AF:

0.0101

Gnomad4 OTH exome

AF:

0.00934

GnomAD4 genome

AF:

0.00726

AC:

1105

AN:

152290

Hom.:

Cov.:

AF XY:

0.00733

AC XY:

546

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00159

Gnomad4 AMR

AF:

0.00608

Gnomad4 ASJ

AF:

0.00749

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0207

Gnomad4 FIN

AF:

0.00320

Gnomad4 NFE

AF:

0.0113

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00981

Hom.:

Bravo

AF:

0.00634

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.00146

AC:

ESP6500EA

AF:

0.0115

AC:

ExAC

AF:

0.00840

AC:

1013

Asia WGS

AF:

0.00751

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 12

Uncertain:1Benign:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 05, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 17, 2011	Glu2588Gln in exon 55 of CDH23: This variant is not expected to have clinical si gnificance due to its occurrence at an equal frequency in the general population (Astuto 2002, Oshima 2008, Kothiyal 2010), its presence in dbSNP at a frequency of 0.9% (8/899) of control chromosomes (rs41281338), and the lack of conservati on of Glu2588 as cow, dog, cat, and opossum all have a glutamine (Gln) at this p osition. -

Usher syndrome type 1D

Benign:2

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2018	This variant is associated with the following publications: (PMID: 21569298, 20146813, 12075507, 18429043, 11138009) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Usher syndrome type 1

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 27, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.84

CADD

Benign

2.8

DANN

Benign

0.49

DEOGEN2

Benign

0.0083

T;T;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.71

T;T;T;T

MetaRNN

Benign

0.0043

T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.84

.;L;.;.

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.050

.;.;.;N

REVEL

Benign

0.072

Sift

Benign

0.58

.;.;.;T

Sift4G

Benign

0.17

T;.;T;T

Polyphen

0.0

.;B;.;.

Vest4

0.14

MVP

0.33

MPC

0.14

ClinPred

0.00013

GERP RS

-2.6

Varity_R

0.097

gMVP

0.23

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