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rs111033483

chr10-71803270-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6BP7BS2

The NM_022124.6(CDH23):c.7722C>T(p.Tyr2574=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00363 in 1,593,284 control chromosomes in the GnomAD database, including 18 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 0.0028 ( 3 hom., cov: 31)
Exomes 𝑓: 0.0037 ( 15 hom. )

Consequence

CDH23
NM_022124.6 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

Conservation

PhyloP100: -3.36
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 -8 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.46).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 10-71803270-C-T is Benign according to our data. Variant chr10-71803270-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46037.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=4, Likely_benign=1}. Variant chr10-71803270-C-T is described in Lovd as [Benign]. Variant chr10-71803270-C-T is described in Lovd as [Likely_benign].
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-3.36 with no splicing effect.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAd at 3 AD,AR,Digenic gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CDH23NM_022124.6 linkuse as main transcriptc.7722C>T p.Tyr2574= synonymous_variant 55/70 ENST00000224721.12
CDH23NM_001171933.1 linkuse as main transcriptc.1002C>T p.Tyr334= synonymous_variant 8/23
CDH23NM_001171934.1 linkuse as main transcriptc.1002C>T p.Tyr334= synonymous_variant 8/22

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CDH23ENST00000224721.12 linkuse as main transcriptc.7722C>T p.Tyr2574= synonymous_variant 55/705 NM_022124.6 P1Q9H251-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00281
AC:
428
AN:
152204
Hom.:
3
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000676
Gnomad AMI
AF:
0.0186
Gnomad AMR
AF:
0.000981
Gnomad ASJ
AF:
0.00317
Gnomad EAS
AF:
0.000385
Gnomad SAS
AF:
0.00124
Gnomad FIN
AF:
0.00122
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00487
Gnomad OTH
AF:
0.00239
GnomAD3 exomes
AF:
0.00255
AC:
539
AN:
210966
Hom.:
4
AF XY:
0.00249
AC XY:
285
AN XY:
114342
show subpopulations
Gnomad AFR exome
AF:
0.000495
Gnomad AMR exome
AF:
0.000808
Gnomad ASJ exome
AF:
0.00399
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000706
Gnomad FIN exome
AF:
0.000666
Gnomad NFE exome
AF:
0.00460
Gnomad OTH exome
AF:
0.00335
GnomAD4 exome
AF:
0.00371
AC:
5351
AN:
1440962
Hom.:
15
Cov.:
34
AF XY:
0.00362
AC XY:
2591
AN XY:
714960
show subpopulations
Gnomad4 AFR exome
AF:
0.000547
Gnomad4 AMR exome
AF:
0.000762
Gnomad4 ASJ exome
AF:
0.00382
Gnomad4 EAS exome
AF:
0.0000260
Gnomad4 SAS exome
AF:
0.000552
Gnomad4 FIN exome
AF:
0.000617
Gnomad4 NFE exome
AF:
0.00449
Gnomad4 OTH exome
AF:
0.00307
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00281
AC:
428
AN:
152322
Hom.:
3
Cov.:
31
AF XY:
0.00255
AC XY:
190
AN XY:
74488
show subpopulations
Gnomad4 AFR
AF:
0.000674
Gnomad4 AMR
AF:
0.000980
Gnomad4 ASJ
AF:
0.00317
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.00124
Gnomad4 FIN
AF:
0.00122
Gnomad4 NFE
AF:
0.00487
Gnomad4 OTH
AF:
0.00236
Alfa
AF:
0.00440
Hom.:
0
Bravo
AF:
0.00270
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:8
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:5
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsMar 11, 2019- -
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2024CDH23: BP4, BP7, BS2 -
Benign, criteria provided, single submitterclinical testingGeneDxMay 09, 2019This variant is associated with the following publications: (PMID: 28912962, 22135276) -
not specified Benign:2
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 17, 2012Tyr2574Tyr in exon 55 of CDH23: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence and has been identified in 0.4% (28/6796) of Eur opean American chromosomes in a broad population by the NHLBI Exome sequencing p roject (http://evs.gs.washington.edu/EVS/; dbSNP rs111033483). -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
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.Oct 21, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.46
Cadd
Benign
1.8
Dann
Benign
0.45

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: rs111033483; hg19: chr10-73563027; COSMIC: COSV56460930; API