rs376497158

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_022124.6(CDH23):​c.9015G>A​(p.Ala3005=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00502 in 1,613,974 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0041 ( 4 hom., cov: 32)
Exomes 𝑓: 0.0051 ( 28 hom. )

Consequence

CDH23
NM_022124.6 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: -0.916
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.7).
BP6
Variant 10-71810507-G-A is Benign according to our data. Variant chr10-71810507-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46065.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=4, Uncertain_significance=2}. Variant chr10-71810507-G-A is described in Lovd as [Benign]. Variant chr10-71810507-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-0.916 with no splicing effect.
BS2
High Homozygotes in GnomAd4 at 4 AD,AR,Digenic gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CDH23NM_022124.6 linkuse as main transcriptc.9015G>A p.Ala3005= synonymous_variant 62/70 ENST00000224721.12 NP_071407.4
LOC124902446XR_007062185.1 linkuse as main transcriptn.1386C>T non_coding_transcript_exon_variant 2/2
CDH23NM_001171933.1 linkuse as main transcriptc.2295G>A p.Ala765= synonymous_variant 15/23 NP_001165404.1
CDH23NM_001171934.1 linkuse as main transcriptc.2295G>A p.Ala765= synonymous_variant 15/22 NP_001165405.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CDH23ENST00000224721.12 linkuse as main transcriptc.9015G>A p.Ala3005= synonymous_variant 62/705 NM_022124.6 ENSP00000224721 P1Q9H251-1

Frequencies

GnomAD3 genomes
AF:
0.00413
AC:
629
AN:
152176
Hom.:
4
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00384
Gnomad AMI
AF:
0.00877
Gnomad AMR
AF:
0.00399
Gnomad ASJ
AF:
0.00115
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00248
Gnomad FIN
AF:
0.000377
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00550
Gnomad OTH
AF:
0.00287
GnomAD3 exomes
AF:
0.00369
AC:
919
AN:
249266
Hom.:
5
AF XY:
0.00384
AC XY:
519
AN XY:
135246
show subpopulations
Gnomad AFR exome
AF:
0.00491
Gnomad AMR exome
AF:
0.00385
Gnomad ASJ exome
AF:
0.000894
Gnomad EAS exome
AF:
0.000111
Gnomad SAS exome
AF:
0.00379
Gnomad FIN exome
AF:
0.000325
Gnomad NFE exome
AF:
0.00470
Gnomad OTH exome
AF:
0.00743
GnomAD4 exome
AF:
0.00511
AC:
7471
AN:
1461680
Hom.:
28
Cov.:
31
AF XY:
0.00505
AC XY:
3669
AN XY:
727126
show subpopulations
Gnomad4 AFR exome
AF:
0.00341
Gnomad4 AMR exome
AF:
0.00398
Gnomad4 ASJ exome
AF:
0.000689
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.00359
Gnomad4 FIN exome
AF:
0.000449
Gnomad4 NFE exome
AF:
0.00588
Gnomad4 OTH exome
AF:
0.00455
GnomAD4 genome
AF:
0.00413
AC:
629
AN:
152294
Hom.:
4
Cov.:
32
AF XY:
0.00427
AC XY:
318
AN XY:
74454
show subpopulations
Gnomad4 AFR
AF:
0.00382
Gnomad4 AMR
AF:
0.00399
Gnomad4 ASJ
AF:
0.00115
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00269
Gnomad4 FIN
AF:
0.000377
Gnomad4 NFE
AF:
0.00548
Gnomad4 OTH
AF:
0.00284
Alfa
AF:
0.00269
Hom.:
0
Bravo
AF:
0.00404
Asia WGS
AF:
0.00202
AC:
7
AN:
3478
EpiCase
AF:
0.00398
EpiControl
AF:
0.00338

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:6
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Benign:3
Benign, criteria provided, single submitterclinical testingGeneDxApr 18, 2014This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 30, 2012Ala3005Ala in exon 62 of CDH23: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located near a splice junction, has been identified in 0.4% (30/6796) of European American ch romosomes from a broad population by the NHLBI Exome sequencing project (http:// evs.gs.washington.edu/EVS/; dbSNP rs41304884), and is reported as benign in one publication (Astuto 2002). -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Apr 16, 2014- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenAug 01, 2024CDH23: BP4, BP7, BS2 -
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. -
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. -
Usher syndrome type 1 Benign:1
Benign, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.70
CADD
Benign
6.7
DANN
Benign
0.70

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: rs376497158; hg19: chr10-73570264; COSMIC: COSV105842320; API