rs757508152

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

Scores

5
12

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 5.08
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]
C10orf105 (HGNC:20304): (chromosome 10 open reading frame 105) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

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
CDH23NM_022124.6 linkuse as main transcriptc.3328A>G p.Ser1110Gly missense_variant 28/70 ENST00000224721.12 NP_071407.4
C10orf105NM_001164375.3 linkuse as main transcriptc.*3164T>C 3_prime_UTR_variant 2/2 ENST00000441508.4 NP_001157847.1
CDH23NM_001171930.2 linkuse as main transcriptc.3328A>G p.Ser1110Gly missense_variant 28/32 NP_001165401.1
C10orf105NM_001168390.2 linkuse as main transcriptc.*3164T>C 3_prime_UTR_variant 2/2 NP_001161862.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CDH23ENST00000224721.12 linkuse as main transcriptc.3328A>G p.Ser1110Gly missense_variant 28/705 NM_022124.6 ENSP00000224721 P1Q9H251-1
C10orf105ENST00000441508.4 linkuse as main transcriptc.*3164T>C 3_prime_UTR_variant 2/21 NM_001164375.3 ENSP00000403151 P1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152268
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000325
AC:
8
AN:
245988
Hom.:
0
AF XY:
0.0000598
AC XY:
8
AN XY:
133872
show subpopulations
Gnomad AFR exome
AF:
0.00
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:
0.0000631
Gnomad OTH exome
AF:
0.000167
GnomAD4 exome
AF:
0.0000144
AC:
21
AN:
1460774
Hom.:
0
Cov.:
31
AF XY:
0.0000151
AC XY:
11
AN XY:
726580
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000448
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:
0.0000162
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152268
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74392
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000264
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.000164
EpiControl
AF:
0.0000594

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 submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJan 29, 2015The 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 providedclinical testingNatera, Inc.Oct 28, 2019- -
Usher syndrome type 1D Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 23, 2022This 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 submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.28
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.032
T;T;T;T;.
Eigen
Benign
0.097
Eigen_PC
Benign
0.20
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Uncertain
0.89
D;D;D;D;T
M_CAP
Benign
0.047
D
MetaRNN
Benign
0.32
T;T;T;T;T
MetaSVM
Benign
-0.46
T
MutationAssessor
Uncertain
2.9
.;.;M;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Benign
0.46
T
REVEL
Uncertain
0.41
Sift4G
Benign
0.16
T;T;.;T;.
Polyphen
0.0050
.;.;B;.;.
Vest4
0.37
MutPred
0.42
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
0.65
ClinPred
0.51
D
GERP RS
4.9
Varity_R
0.34
gMVP
0.42

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

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.

Other links and lift over

dbSNP: rs757508152; hg19: chr10-73472529; API