rs397517342

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong

The NM_022124.6(CDH23):c.5712G>A(p.Thr1904Thr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

CDH23
NM_022124.6 splice_region, synonymous

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 0.660

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 Pathogenic. Variant got 12 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

PP5

Variant 10-71785100-G-A is Pathogenic according to our data. Variant chr10-71785100-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 45989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71785100-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6 link	c.5712G>A	p.Thr1904Thr	splice_region_variant, synonymous_variant	Exon 43 of 70	ENST00000224721.12	NP_071407.4	Q9H251-1Q6P152

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12 link	c.5712G>A	p.Thr1904Thr	splice_region_variant, synonymous_variant	Exon 43 of 70	5	NM_022124.6	ENSP00000224721.9		Q9H251-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000805

AC:

AN:

248502

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134810

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000889

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1460782

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726726

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

CDH23-related disorder

Pathogenic:1

Feb 15, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CDH23 c.5712G>A variant is not predicted to result in an amino acid change (p.=). This variant occurs at the last nucleotide of exon 43 and is predicted to impact splicing (Alamut Visual Plus v1.6.1). This variant was reported in the homozygous or compound heterozygous state in individuals with Usher syndrome or inherited retinal disease (von Brederlow et al. 2002. PubMed ID: 11857743; Vozzi et al. 2011. PubMed ID: 21738395; Supplemental Table, Holtan et al. 2019. PubMed ID: 31429209; Table S1, Karali et al. 2022. PubMed ID: 36460718). In vitro exon skipping experiments showed that the c.5712G>A variant results in skipping of exon 43, which does not alter the reading frame but would result in the loss of 70 amino acids (von Brederlow et al. 2002. PubMed ID: 11857743). This variant is reported in 0.0065% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic. -

Pituitary adenoma 5, multiple types

Pathogenic:1

Aug 23, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1

Pathogenic:1

Jan 22, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Jul 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 1904 of the CDH23 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CDH23 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs397517342, gnomAD 0.007%). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 42, but is expected to preserve the integrity of the reading-frame (PMID: 11857743). ClinVar contains an entry for this variant (Variation ID: 45989). This variant has been observed in individual(s) with Usher syndrome (PMID: 11857743, 21738395). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. -

Rare genetic deafness

Pathogenic:1

Feb 01, 2024

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5712G>A (p.Thr1904Thr) variant in CDH23 has been identified in 4 individuals with Usher syndrome (1 homozygote and 3 compound heterozygotes with another disease causing variant in CDH23) and segregated with disease in 2 affected relatives from 2 families (von Brederlow 2002 PMID: 11857743, Vozzi 2011 PMID: 21738395, LMM internal data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 45989) and has been identified in 0.002% (1/41468) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This variant is located in the last base of the exon, which is part of the 5’ splice region. Computational tools predict a splicing impact and exon-trapping assays reveal that the variant causes skipping of exon 43 which does not result in the disruption of the reading frame (von Brederlow 2002 PMID: 11857743). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome. ACMG/AMP Criteria applied: PM3_Strong, PS3_Moderate, PP1_Moderate, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.98

SpliceAI score (max)

0.44

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.44

Position offset: 0

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