chr10-71707035-G-C
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_022124.6(CDH23):āc.3092G>Cā(p.Ser1031Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000311 in 1,605,370 control chromosomes in the GnomAD database, with no homozygous occurrence. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Synonymous variant affecting the same amino acid position (i.e. S1031S) has been classified as Uncertain significance.
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 33)
Exomes š: 0.0000028 ( 0 hom. )
Consequence
CDH23
NM_022124.6 missense
NM_022124.6 missense
Scores
2
3
10
Clinical Significance
Conservation
PhyloP100: 9.96
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| CDH23 | NM_022124.6 | c.3092G>C | p.Ser1031Thr | missense_variant | 26/70 | ENST00000224721.12 | |
| CDH23 | NM_001171930.2 | c.3092G>C | p.Ser1031Thr | missense_variant | 26/32 | ||
| CDH23 | NM_001171931.2 | c.3092G>C | p.Ser1031Thr | missense_variant | 26/26 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CDH23 | ENST00000224721.12 | c.3092G>C | p.Ser1031Thr | missense_variant | 26/70 | 5 | NM_022124.6 | P1 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152252Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.00000275 AC: 4AN: 1453118Hom.: 0 Cov.: 31 AF XY: 0.00000416 AC XY: 3AN XY: 721962
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GnomAD4 genome 0.00000657 AC: 1AN: 152252Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74384
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 25, 2022 | This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 1031 of the CDH23 protein (p.Ser1031Thr). This variant is present in population databases (rs397517320, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CDH23-related conditions. ClinVar contains an entry for this variant (Variation ID: 45909). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CDH23 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 23, 2018 | The p.Ser1031Thr variant (rs397517320) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) identified on a single chromosome out of 30,944, and has been reported to the ClinVar database as a variant of uncertain significance (Variation ID: 45909). The serine at position 1031 is highly conserved up to zebrafish considering 12 species (Alamut v2.10) and computational analyses of the effects of the p.Ser1031Thr variant on protein structure and function provide conflicting results (SIFT:tolerated, MutationTaster: disease causing, PolyPhen-2:possibly damaging). Altogether, there is not enough evidence to classify the p.Ser1031Thr variant with certainty. - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 11, 2014 | The Ser1031Thr variant in CDH23 has not been previously reported in individuals with hearing loss and was absent from large population studies. Computational pr ediction tools and conservation analysis suggest that this variant may impact th e protein, though this information is not predictive enough to determine pathoge nicity. In summary, the clinical significance of the Ser1031Thr variant is uncer tain. - |
Inborn genetic diseases Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 08, 2022 | The c.3092G>C (p.S1031T) alteration is located in exon 26 (coding exon 25) of the CDH23 gene. This alteration results from a G to C substitution at nucleotide position 3092, causing the serine (S) at amino acid position 1031 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Usher syndrome type 1D Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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. - |
Usher syndrome type 1 Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Autosomal recessive nonsyndromic hearing loss 12 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T;T;.;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
T;T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
T
Sift4G
Benign
T;T;.;D;T;.
Polyphen
0.72
.;.;P;.;.;.
Vest4
MutPred
Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);
MVP
ClinPred
D
GERP RS
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at