chr10-71712692-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_022124.6(CDH23):​c.3248C>T​(p.Thr1083Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,613,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. T1083R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

3
11
3

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 6.15

Publications

4 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]
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 was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.772

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CDH23NM_022124.6 linkc.3248C>T p.Thr1083Met missense_variant Exon 28 of 70 ENST00000224721.12 NP_071407.4 Q9H251-1Q6P152
C10orf105NM_001164375.3 linkc.*3244G>A 3_prime_UTR_variant Exon 2 of 2 ENST00000441508.4 NP_001157847.1 Q8TEF2
CDH23NM_001171930.2 linkc.3248C>T p.Thr1083Met missense_variant Exon 28 of 32 NP_001165401.1 Q9H251A0A087WYR8Q6P152
C10orf105NM_001168390.2 linkc.*3244G>A 3_prime_UTR_variant Exon 2 of 2 NP_001161862.1 Q8TEF2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CDH23ENST00000224721.12 linkc.3248C>T p.Thr1083Met missense_variant Exon 28 of 70 5 NM_022124.6 ENSP00000224721.9 Q9H251-1
C10orf105ENST00000441508.4 linkc.*3244G>A 3_prime_UTR_variant Exon 2 of 2 1 NM_001164375.3 ENSP00000403151.2 Q8TEF2

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152248
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000169
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000282
AC:
7
AN:
248424
AF XY:
0.0000296
show subpopulations
Gnomad AFR exome
AF:
0.000195
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000557
Gnomad FIN exome
AF:
0.0000465
Gnomad NFE exome
AF:
0.0000178
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000116
AC:
17
AN:
1461304
Hom.:
0
Cov.:
31
AF XY:
0.0000151
AC XY:
11
AN XY:
726926
show subpopulations
African (AFR)
AF:
0.000179
AC:
6
AN:
33478
American (AMR)
AF:
0.0000447
AC:
2
AN:
44716
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39700
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86240
European-Finnish (FIN)
AF:
0.0000377
AC:
2
AN:
53064
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.00000450
AC:
5
AN:
1111838
Other (OTH)
AF:
0.00
AC:
0
AN:
60366
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.463
Heterozygous variant carriers
0
2
4
6
8
10
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152248
Hom.:
0
Cov.:
33
AF XY:
0.0000672
AC XY:
5
AN XY:
74374
show subpopulations
African (AFR)
AF:
0.000169
AC:
7
AN:
41468
American (AMR)
AF:
0.00
AC:
0
AN:
15282
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5196
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4838
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10622
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68052
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.518
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000341
Hom.:
0
Bravo
AF:
0.0000189
ExAC
AF:
0.0000248
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Jul 26, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1083 of the CDH23 protein (p.Thr1083Met). This variant is present in population databases (rs756165682, gnomAD 0.03%). 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: 843647). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C65"). 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. -

Jan 17, 2025
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Usher syndrome type 1 Uncertain:1
Mar 17, 2020
Natera, Inc.
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Uncertain
0.029
T
BayesDel_noAF
Uncertain
0.080
CADD
Uncertain
26
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.034
T;T;T;T;.
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.60
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.95
D;D;D;D;D
M_CAP
Pathogenic
0.50
D
MetaRNN
Pathogenic
0.77
D;D;D;D;D
MetaSVM
Uncertain
-0.099
T
MutationAssessor
Uncertain
2.2
.;.;M;.;.
PhyloP100
6.1
PrimateAI
Uncertain
0.50
T
REVEL
Uncertain
0.56
Sift4G
Uncertain
0.0030
D;D;.;D;.
Polyphen
0.99
.;.;D;.;.
Vest4
0.81
MutPred
0.54
Loss of catalytic residue at T1083 (P = 0.0138);Loss of catalytic residue at T1083 (P = 0.0138);Loss of catalytic residue at T1083 (P = 0.0138);Loss of catalytic residue at T1083 (P = 0.0138);Loss of catalytic residue at T1083 (P = 0.0138);
MVP
0.89
ClinPred
0.83
D
GERP RS
4.9
Varity_R
0.19
gMVP
0.62
Mutation Taster
=30/70
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: rs756165682; hg19: chr10-73472449; COSMIC: COSV56452031; API