chr10-71724072-G-A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_022124.6(CDH23):​c.3397G>A​(p.Glu1133Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000596 in 1,560,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E1133E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

CDH23
NM_022124.6 missense

Scores

4
13

Clinical Significance

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

Conservation

PhyloP100: 5.24
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: Likely_benign. The variant received -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.034316838).
BS1
Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000575 (81/1408096) while in subpopulation EAS AF = 0.00134 (49/36558). AF 95% confidence interval is 0.00104. There are 0 homozygotes in GnomAdExome4. There are 35 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CDH23NM_022124.6 linkc.3397G>A p.Glu1133Lys missense_variant Exon 29 of 70 ENST00000224721.12 NP_071407.4 Q9H251-1Q6P152
CDH23NM_001171930.2 linkc.3397G>A p.Glu1133Lys missense_variant Exon 29 of 32 NP_001165401.1 Q9H251A0A087WYR8Q6P152
C10orf105NM_001168390.2 linkc.-5-7730C>T intron_variant Intron 1 of 1 NP_001161862.1 Q8TEF2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CDH23ENST00000224721.12 linkc.3397G>A p.Glu1133Lys missense_variant Exon 29 of 70 5 NM_022124.6 ENSP00000224721.9 Q9H251-1

Frequencies

GnomAD3 genomes
AF:
0.0000788
AC:
12
AN:
152188
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000577
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000215
AC:
36
AN:
167448
AF XY:
0.000169
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00232
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000734
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000575
AC:
81
AN:
1408096
Hom.:
0
Cov.:
32
AF XY:
0.0000503
AC XY:
35
AN XY:
695254
show subpopulations
Gnomad4 AFR exome
AF:
0.0000312
AC:
1
AN:
32098
Gnomad4 AMR exome
AF:
0.000109
AC:
4
AN:
36752
Gnomad4 ASJ exome
AF:
0.0000396
AC:
1
AN:
25244
Gnomad4 EAS exome
AF:
0.00134
AC:
49
AN:
36558
Gnomad4 SAS exome
AF:
0.0000251
AC:
2
AN:
79624
Gnomad4 FIN exome
AF:
0.00
AC:
0
AN:
49836
Gnomad4 NFE exome
AF:
0.0000148
AC:
16
AN:
1083856
Gnomad4 Remaining exome
AF:
0.000103
AC:
6
AN:
58420
Heterozygous variant carriers
0
4
9
13
18
22
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
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:
0.0000788
AC:
12
AN:
152188
Hom.:
0
Cov.:
33
AF XY:
0.0000673
AC XY:
5
AN XY:
74346
show subpopulations
Gnomad4 AFR
AF:
0.00
AC:
0
AN:
0
Gnomad4 AMR
AF:
0.000262
AC:
0.000261746
AN:
0.000261746
Gnomad4 ASJ
AF:
0.00
AC:
0
AN:
0
Gnomad4 EAS
AF:
0.000577
AC:
0.000576923
AN:
0.000576923
Gnomad4 SAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 FIN
AF:
0.00
AC:
0
AN:
0
Gnomad4 NFE
AF:
0.0000735
AC:
0.0000735121
AN:
0.0000735121
Gnomad4 OTH
AF:
0.00
AC:
0
AN:
0
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
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:
0.000112
Hom.:
0
Bravo
AF:
0.000181
ExAC
AF:
0.0000957
AC:
11

ClinVar

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

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 12;C1832845:Usher syndrome type 1D;C4539685:Pituitary adenoma 5, multiple types Uncertain:1
Jan 19, 2022
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Uncertain:1
Dec 13, 2009
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Pituitary adenoma 5, multiple types Uncertain:1
Aug 23, 2022
Baylor Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Usher syndrome type 1 Uncertain:1
Sep 16, 2020
Natera, Inc.
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

not provided Benign:1
Dec 23, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.36
T
BayesDel_noAF
Benign
-0.29
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.022
T;T;T;T
Eigen
Benign
0.025
Eigen_PC
Benign
0.13
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.95
D;D;D;D
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.034
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.67
.;.;N;.
PrimateAI
Uncertain
0.64
T
REVEL
Benign
0.17
Sift4G
Benign
0.14
T;T;.;T
Polyphen
0.32
.;.;B;.
Vest4
0.38
MutPred
0.64
.;Gain of MoRF binding (P = 0.0078);Gain of MoRF binding (P = 0.0078);Gain of MoRF binding (P = 0.0078);
MVP
0.83
ClinPred
0.14
T
GERP RS
4.9
Varity_R
0.13
gMVP
0.32
Mutation Taster
=76/24
polymorphism

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: rs111033509; hg19: chr10-73483829; COSMIC: COSV56457754; COSMIC: COSV56457754; API