rs757508152
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The ENST00000441508.4(C10orf105):c.*3164T>C variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.0000143 in 1,613,042 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000014 ( 0 hom. )
Consequence
C10orf105
ENST00000441508.4 3_prime_UTR
ENST00000441508.4 3_prime_UTR
Scores
5
12
Clinical Significance
Conservation
PhyloP100: 5.08
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 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3193648).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.3328A>G | p.Ser1110Gly | missense_variant | 28/70 | ENST00000224721.12 | NP_071407.4 | |
C10orf105 | NM_001164375.3 | c.*3164T>C | 3_prime_UTR_variant | 2/2 | ENST00000441508.4 | NP_001157847.1 | ||
CDH23 | NM_001171930.2 | c.3328A>G | p.Ser1110Gly | missense_variant | 28/32 | NP_001165401.1 | ||
C10orf105 | NM_001168390.2 | c.*3164T>C | 3_prime_UTR_variant | 2/2 | NP_001161862.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.3328A>G | p.Ser1110Gly | missense_variant | 28/70 | 5 | NM_022124.6 | ENSP00000224721 | P1 | |
C10orf105 | ENST00000441508.4 | c.*3164T>C | 3_prime_UTR_variant | 2/2 | 1 | NM_001164375.3 | ENSP00000403151 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152268Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000325 AC: 8AN: 245988Hom.: 0 AF XY: 0.0000598 AC XY: 8AN XY: 133872
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GnomAD4 exome AF: 0.0000144 AC: 21AN: 1460774Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 726580
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152268Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74392
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 29, 2015 | The p.Ser1110Gly variant in CDH23 has not been previously reported in individual s with hearing loss, but has been identified in 2/60180 of European (Non-Finnish ) chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstit ute.org). Computational prediction tools and conservation analysis do not provid e strong support for or against an impact to the protein. In summary, the clinic al significance of the p.Ser1110Gly variant is uncertain. - |
Usher syndrome type 1 Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 28, 2019 | - - |
Usher syndrome type 1D Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 23, 2022 | This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 1110 of the CDH23 protein (p.Ser1110Gly). This variant is present in population databases (rs757508152, gnomAD 0.006%). 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: 228492). 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. - |
Autosomal recessive nonsyndromic hearing loss 12 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 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
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
.;.;M;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Benign
T
REVEL
Uncertain
Sift4G
Benign
T;T;.;T;.
Polyphen
0.0050
.;.;B;.;.
Vest4
MutPred
Loss of phosphorylation at S1110 (P = 0.0485);Loss of phosphorylation at S1110 (P = 0.0485);Loss of phosphorylation at S1110 (P = 0.0485);Loss of phosphorylation at S1110 (P = 0.0485);Loss of phosphorylation at S1110 (P = 0.0485);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
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