chr10-71712674-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4_Moderate

The NM_022124.6(CDH23):​c.3230C>T​(p.Pro1077Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000824 in 1,613,634 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1077R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

2
8
7

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 7.88
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 0 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_022124.6
BP4
Computational evidence support a benign effect (MetaRNN=0.07883695).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CDH23NM_022124.6 linkuse as main transcriptc.3230C>T p.Pro1077Leu missense_variant 28/70 ENST00000224721.12
C10orf105NM_001164375.3 linkuse as main transcriptc.*3262G>A 3_prime_UTR_variant 2/2 ENST00000441508.4
CDH23NM_001171930.2 linkuse as main transcriptc.3230C>T p.Pro1077Leu missense_variant 28/32
C10orf105NM_001168390.2 linkuse as main transcriptc.*3262G>A 3_prime_UTR_variant 2/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CDH23ENST00000224721.12 linkuse as main transcriptc.3230C>T p.Pro1077Leu missense_variant 28/705 NM_022124.6 P1Q9H251-1
C10orf105ENST00000441508.4 linkuse as main transcriptc.*3262G>A 3_prime_UTR_variant 2/21 NM_001164375.3 P1

Frequencies

GnomAD3 genomes
AF:
0.000381
AC:
58
AN:
152242
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00128
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000125
AC:
31
AN:
248514
Hom.:
0
AF XY:
0.0000592
AC XY:
8
AN XY:
135036
show subpopulations
Gnomad AFR exome
AF:
0.00156
Gnomad AMR exome
AF:
0.000116
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:
0.0000267
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000513
AC:
75
AN:
1461274
Hom.:
0
Cov.:
31
AF XY:
0.0000440
AC XY:
32
AN XY:
726922
show subpopulations
Gnomad4 AFR exome
AF:
0.00137
Gnomad4 AMR exome
AF:
0.000157
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:
0.0000117
Gnomad4 OTH exome
AF:
0.000149
GnomAD4 genome
AF:
0.000381
AC:
58
AN:
152360
Hom.:
0
Cov.:
33
AF XY:
0.000389
AC XY:
29
AN XY:
74508
show subpopulations
Gnomad4 AFR
AF:
0.00127
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000999
Hom.:
0
Bravo
AF:
0.000476
ESP6500AA
AF:
0.000969
AC:
4
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000124
AC:
15
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingInvitaeJan 16, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxApr 28, 2021In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineNov 25, 2015The p.Pro1077Leu variant in CDH23 has been identified by our laboratory in one i ndividual with sensorineural hearing loss, who did not carry a second CDH23 vari ant (LMM unpublished data). The variant has been identified in 0.16% (15/9416) o f African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org; dbSNP rs202101019); however, this frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation a nalysis suggest that this variant may impact the protein, though this informatio n is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Pro1077Leu variant is uncertain. -
Usher syndrome type 1 Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Mar 03, 2020- -
Retinal dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBlueprint GeneticsOct 22, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Benign
-0.067
T
BayesDel_noAF
Uncertain
0.11
CADD
Uncertain
24
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.025
T;T;T;T;.
Eigen
Uncertain
0.51
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.94
D;D;D;D;D
M_CAP
Pathogenic
0.43
D
MetaRNN
Benign
0.079
T;T;T;T;T
MetaSVM
Uncertain
-0.26
T
MutationAssessor
Benign
0.48
.;.;N;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.53
T
REVEL
Benign
0.19
Sift4G
Uncertain
0.0050
D;D;.;D;.
Polyphen
0.28
.;.;B;.;.
Vest4
0.91
MVP
0.80
ClinPred
0.080
T
GERP RS
4.9
Varity_R
0.37
gMVP
0.57

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs202101019; hg19: chr10-73472431; API