10-71706971-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_022124.6(CDH23):​c.3028C>A​(p.Arg1010Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1010C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

CDH23
NM_022124.6 missense

Scores

2
11
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.06

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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CDH23NM_022124.6 linkc.3028C>A p.Arg1010Ser missense_variant Exon 26 of 70 ENST00000224721.12 NP_071407.4 Q9H251-1Q6P152
CDH23NM_001171930.2 linkc.3028C>A p.Arg1010Ser missense_variant Exon 26 of 32 NP_001165401.1 Q9H251A0A087WYR8Q6P152
CDH23NM_001171931.2 linkc.3028C>A p.Arg1010Ser missense_variant Exon 26 of 26 NP_001165402.1 Q9H251Q8N5B3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CDH23ENST00000224721.12 linkc.3028C>A p.Arg1010Ser missense_variant Exon 26 of 70 5 NM_022124.6 ENSP00000224721.9 Q9H251-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 03, 2014
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The Arg1010Ser variant in CDH23 has not been previously reported in individuals with hearing loss or from large population studies. Computational prediction too ls and conservation analyses suggest this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summa ry, additional information is needed to fully assess the clinical significance o f this variant. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.56
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.30
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.014
T;T;T;.;T;.
Eigen
Uncertain
0.36
Eigen_PC
Uncertain
0.29
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.92
D;D;D;D;D;D
M_CAP
Uncertain
0.093
D
MetaRNN
Uncertain
0.74
D;D;D;D;D;D
MetaSVM
Benign
-0.37
T
MutationAssessor
Benign
0.25
.;.;N;.;.;.
PhyloP100
5.1
PrimateAI
Uncertain
0.60
T
REVEL
Uncertain
0.31
Sift4G
Uncertain
0.0070
D;T;.;T;D;.
Polyphen
0.97
.;.;D;.;.;.
Vest4
0.84
MutPred
0.53
Gain of disorder (P = 0.0582);Gain of disorder (P = 0.0582);Gain of disorder (P = 0.0582);Gain of disorder (P = 0.0582);Gain of disorder (P = 0.0582);Gain of disorder (P = 0.0582);
MVP
0.71
ClinPred
0.95
D
GERP RS
5.3
Varity_R
0.44
gMVP
0.65
Mutation Taster
=47/53
disease causing

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

Other links and lift over

dbSNP: rs727505173; hg19: chr10-73466728; API