Variant rs367928692 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_022124.6(CDH23):c.6050-9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000451 in 1,597,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

CDH23
NM_022124.6 intron

Scores

Splicing: ADA: 0.9991

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 0.361

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 Likely_pathogenic. Variant got 8 ACMG points.

PP5

Variant 10-71791123-G-A is Pathogenic according to our data. Variant chr10-71791123-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 46001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71791123-G-A is described in Lovd as [Pathogenic]. Variant chr10-71791123-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6 linkuse as main transcript	c.6050-9G>A		intron_variant		ENST00000224721.12	NP_071407.4	Q9H251-1Q6P152

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 linkuse as main transcript	c.6050-9G>A		intron_variant		5	NM_022124.6	ENSP00000224721.9		Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000489

AC:

AN:

225026

Hom.:

AF XY:

0.0000246

AC XY:

AN XY:

122138

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000143

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000593

Gnomad OTH exome

AF:

0.000178

GnomAD4 exome

AF:

0.0000436

AC:

AN:

1445292

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

717420

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000770

Gnomad4 SAS exome

AF:

0.000131

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000408

Gnomad4 OTH exome

AF:

0.0000669

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0304

Hom.:

776

Bravo

AF:

0.0000416

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2023	Published in vivo and in vitro studies demonstrate abnormal gene splicing with an insertion of a 7bp intronic sequence, leading to absence of expression (Vache et al., 2010; Valero et al., 2019); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 25404053, 11857743, 31546658, 32467589, 24498627, 20513143, 21940737, 30303587, 31980526, 35020051) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	This sequence change falls in intron 46 of the CDH23 gene. It does not directly change the encoded amino acid sequence of the CDH23 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs367928692, gnomAD 0.01%). This variant has been observed in individuals with Usher syndrome (PMID: 11857743, 12075507, 17407589, 18429043, 21569298, 21940737, 25404053). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS45-9G>A. ClinVar contains an entry for this variant (Variation ID: 46001). Studies have shown that this variant results in insertion of 7 nucleotides from intron 46 and introduces a premature termination codon (PMID: 11857743, 20513143). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Aug 10, 2015	- -

Autosomal recessive nonsyndromic hearing loss 12;C1832845:Usher syndrome type 1D;C4539685:Pituitary adenoma 5, multiple types

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

CDH23-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 07, 2024

The CDH23 c.6050-9G>A variant is predicted to interfere with splicing. This variant has been reported to be causative for nonsyndromic hearing loss and Usher syndrome (von Brederlow et al. 2002. PubMed ID: 11857743; Aparisi et al. 2014. PubMed ID: 25404053; Besnard et al. 2014. PubMed ID: 24498627). In vitro characterization indicates that this variant creates a novel acceptor site and results in a frameshift causing addition of seven nucleotides in exon 46 (Valero et al. 2019. PubMed ID: 31546658). This variant is reported in 0.014% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic. -

Pituitary adenoma 5, multiple types

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 19, 2024

- -

Usher syndrome type 1

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Hearing loss, autosomal recessive

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

- -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 03, 2015

The c.6050-9G>A variant in CHD23 has been reported in >20 individuals with Usher syndrome who were homozygous or compound heterozygous for the variant. The vari ant segregated with disease in 3 affected relatives from 3 families (von Brederl ow 2002, Astuto 2002, Pennings 2004, Roux 2006, Ebermann 2007, Oshima 2008, Jaij o 2009, Vache 2010, Kimberling 2010, Bonnet 2011, Roux 2011, Schultz 2011, Besna rd 2014). This variant has been identified in 3/28260 European chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs36 7928692). Although this variant has been seen in the general population, its fre quency is low enough to be consistent with a recessive carrier frequency. This v ariant is located in the 3' splice region. In vitro functional studies provide e vidence that the c.6050-9G>A variant impacts splicing (Von Brederlow 2002, Vache 2010). In summary, this variant meets our criteria to be classified as pathogen ic for Usher syndrome in an autosomal recessive manner. ACMG/AMP codes applied: PM3_VeryStrong; PM2; PS3_Moderate; PP4. -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

DANN

Benign

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.99

Position offset: 2

DS_AL_spliceai

0.83

Position offset: 9

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

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