10-71646691-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_022124.6(CDH23):​c.1449+74G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,613,648 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0082 ( 23 hom., cov: 33)
Exomes 𝑓: 0.00093 ( 22 hom. )

Consequence

CDH23
NM_022124.6 intron

Scores

1
11

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.0780
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.002867937).
BP6
Variant 10-71646691-G-T is Benign according to our data. Variant chr10-71646691-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 46543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-71646691-G-T is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00818 (1246/152286) while in subpopulation AFR AF= 0.0287 (1194/41538). AF 95% confidence interval is 0.0274. There are 23 homozygotes in gnomad4. There are 574 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 23 AD,AR,Digenic gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CDH23NM_022124.6 linkuse as main transcriptc.1449+74G>T intron_variant ENST00000224721.12 NP_071407.4
CDH23NM_052836.4 linkuse as main transcriptc.1523G>T p.Cys508Phe missense_variant 14/14 NP_443068.1
CDH23NM_001171930.2 linkuse as main transcriptc.1449+74G>T intron_variant NP_001165401.1
CDH23NM_001171931.2 linkuse as main transcriptc.1449+74G>T intron_variant NP_001165402.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CDH23ENST00000224721.12 linkuse as main transcriptc.1449+74G>T intron_variant 5 NM_022124.6 ENSP00000224721 P1Q9H251-1

Frequencies

GnomAD3 genomes
AF:
0.00817
AC:
1243
AN:
152168
Hom.:
23
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0288
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00242
Gnomad ASJ
AF:
0.00115
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00191
GnomAD3 exomes
AF:
0.00221
AC:
546
AN:
247558
Hom.:
13
AF XY:
0.00176
AC XY:
237
AN XY:
134426
show subpopulations
Gnomad AFR exome
AF:
0.0311
Gnomad AMR exome
AF:
0.00116
Gnomad ASJ exome
AF:
0.000398
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000117
Gnomad OTH exome
AF:
0.000828
GnomAD4 exome
AF:
0.000929
AC:
1357
AN:
1461362
Hom.:
22
Cov.:
31
AF XY:
0.000776
AC XY:
564
AN XY:
726894
show subpopulations
Gnomad4 AFR exome
AF:
0.0313
Gnomad4 AMR exome
AF:
0.00134
Gnomad4 ASJ exome
AF:
0.000918
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000927
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000756
Gnomad4 OTH exome
AF:
0.00209
GnomAD4 genome
AF:
0.00818
AC:
1246
AN:
152286
Hom.:
23
Cov.:
33
AF XY:
0.00771
AC XY:
574
AN XY:
74460
show subpopulations
Gnomad4 AFR
AF:
0.0287
Gnomad4 AMR
AF:
0.00242
Gnomad4 ASJ
AF:
0.00115
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00189
Alfa
AF:
0.00427
Hom.:
5
Bravo
AF:
0.00943
ESP6500AA
AF:
0.0260
AC:
103
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00270
AC:
326
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 30, 2012Cys508Phe in Exon 14 of CDH23: This variant is not expected to have clinical sig nificance because it has been identified in 2.7% (88/3278) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs115450602). -
not provided Benign:2
Likely benign, criteria provided, single submitterclinical testingGeneDxOct 17, 2018- -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
CDH23-related disorder Benign:1
Benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJul 24, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.53
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
3.9
DANN
Benign
0.94
Eigen
Benign
-0.56
Eigen_PC
Benign
-0.69
FATHMM_MKL
Benign
0.084
N
LIST_S2
Benign
0.34
T;T
MetaRNN
Benign
0.0029
T;T
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
0.52
D;D;N;N
REVEL
Benign
0.081
Sift4G
Pathogenic
0.0
D;D
Polyphen
0.90
P;.
Vest4
0.18
MVP
0.39
ClinPred
0.0074
T
GERP RS
2.3

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: rs115450602; hg19: chr10-73406448; API