rs111583276

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_022124.6(CDH23):​c.8980-12C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,613,518 control chromosomes in the GnomAD database, including 4 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 0.00099 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0017 ( 4 hom. )

Consequence

CDH23
NM_022124.6 splice_polypyrimidine_tract, intron

Scores

2
Splicing: ADA: 0.4466
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 0.905
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 -7 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.44).
BP6
Variant 10-71810460-C-T is Benign according to our data. Variant chr10-71810460-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46061.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2, Likely_benign=3}. Variant chr10-71810460-C-T is described in Lovd as [Benign].
BS2
High Homozygotes in GnomAdExome4 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.8980-12C>T splice_polypyrimidine_tract_variant, intron_variant ENST00000224721.12 NP_071407.4
LOC124902446XR_007062185.1 linkuse as main transcriptn.1433G>A non_coding_transcript_exon_variant 2/2
CDH23NM_001171933.1 linkuse as main transcriptc.2260-12C>T splice_polypyrimidine_tract_variant, intron_variant NP_001165404.1
CDH23NM_001171934.1 linkuse as main transcriptc.2260-12C>T splice_polypyrimidine_tract_variant, intron_variant NP_001165405.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CDH23ENST00000224721.12 linkuse as main transcriptc.8980-12C>T splice_polypyrimidine_tract_variant, intron_variant 5 NM_022124.6 ENSP00000224721 P1Q9H251-1

Frequencies

GnomAD3 genomes
AF:
0.000992
AC:
151
AN:
152188
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000193
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000981
Gnomad ASJ
AF:
0.00173
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00228
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00160
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.00137
AC:
341
AN:
249024
Hom.:
1
AF XY:
0.00160
AC XY:
216
AN XY:
135186
show subpopulations
Gnomad AFR exome
AF:
0.0000646
Gnomad AMR exome
AF:
0.000812
Gnomad ASJ exome
AF:
0.00169
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00291
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00176
Gnomad OTH exome
AF:
0.00116
GnomAD4 exome
AF:
0.00172
AC:
2508
AN:
1461212
Hom.:
4
Cov.:
31
AF XY:
0.00184
AC XY:
1339
AN XY:
726920
show subpopulations
Gnomad4 AFR exome
AF:
0.000269
Gnomad4 AMR exome
AF:
0.000962
Gnomad4 ASJ exome
AF:
0.00138
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00296
Gnomad4 FIN exome
AF:
0.000169
Gnomad4 NFE exome
AF:
0.00184
Gnomad4 OTH exome
AF:
0.00171
GnomAD4 genome
AF:
0.000991
AC:
151
AN:
152306
Hom.:
0
Cov.:
32
AF XY:
0.000846
AC XY:
63
AN XY:
74470
show subpopulations
Gnomad4 AFR
AF:
0.000192
Gnomad4 AMR
AF:
0.000980
Gnomad4 ASJ
AF:
0.00173
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00228
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.00160
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.00140
Hom.:
0
Bravo
AF:
0.000933
Asia WGS
AF:
0.00144
AC:
5
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:3
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Likely benign, criteria provided, single submitterclinical testingGeneDxOct 21, 2020- -
Likely benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 18, 2020- -
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. -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineFeb 26, 2015c.8980-12C>T in intron 61 of CDH23: This variant is not expected to have clinica l significance because a C>T change at this position does not diverge from the s plice consensus sequence and is therefore unlikely to impact splicing. It has be en identified in 0.3% (57/16364) of South Asian chromosomes by the Exome Aggrega tion Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs111583276). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.44
CADD
Benign
14
DANN
Benign
0.70

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.45
dbscSNV1_RF
Benign
0.57
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: rs111583276; hg19: chr10-73570217; API