chr10-71802897-G-C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_022124.6(CDH23):​c.7483-1G>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

CDH23
NM_022124.6 splice_acceptor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 9.38

Publications

0 publications found
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 Gene-Disease associations (from GenCC):
  • autosomal recessive nonsyndromic hearing loss 12
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
  • nonsyndromic genetic hearing loss
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
  • Usher syndrome type 1
    Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
  • Usher syndrome type 1D
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
  • hearing loss, autosomal recessive
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.017685046 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.4, offset of 42, new splice context is: tcaatgactgccggccacAGttc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 10-71802897-G-C is Pathogenic according to our data. Variant chr10-71802897-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CDH23NM_022124.6 linkc.7483-1G>C splice_acceptor_variant, intron_variant Intron 53 of 69 ENST00000224721.12 NP_071407.4 Q9H251-1Q6P152
CDH23NM_001171933.1 linkc.763-1G>C splice_acceptor_variant, intron_variant Intron 6 of 22 NP_001165404.1 Q9H251-7
CDH23NM_001171934.1 linkc.763-1G>C splice_acceptor_variant, intron_variant Intron 6 of 21 NP_001165405.1 Q9H251-9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CDH23ENST00000224721.12 linkc.7483-1G>C splice_acceptor_variant, intron_variant Intron 53 of 69 5 NM_022124.6 ENSP00000224721.9 Q9H251-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Aug 23, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

ClinVar contains an entry for this variant (Variation ID: 228329). This variant has not been reported in the literature in individuals affected with CDH23-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 53 of the CDH23 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CDH23 are known to be pathogenic (PMID: 11138009, 21940737). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. -

Rare genetic deafness Pathogenic:1
Feb 26, 2015
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.7483-1G>C variant in CDH23 has not been previously reported in individuals with hearing loss or in large population studies. This variant occurs in the in variant region (+/- 1,2) of the splice consensus sequence and is predicted to ca use altered splicing leading to an abnormal or absent protein. In summary, this variant meets our criteria to be classified as pathogenic for Usher syndrome in an autosomal recessive manner (http://www.partners.org/personalizedmedicine/LMM) based upon its predicted impact on the protein and low frequency in the general population. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.34
CADD
Pathogenic
34
DANN
Uncertain
1.0
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.1
FATHMM_MKL
Pathogenic
1.0
D
PhyloP100
9.4
GERP RS
5.1
Mutation Taster
=0/100
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.40
Position offset: 14
DS_AL_spliceai
0.99
Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs876657682; hg19: chr10-73562654; API