rs80028391
Positions:
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2
The NM_022124.6(CDH23):c.3574G>A(p.Val1192Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00163 in 1,612,846 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0091 ( 29 hom., cov: 33)
Exomes 𝑓: 0.00085 ( 22 hom. )
Consequence
CDH23
NM_022124.6 missense
NM_022124.6 missense
Scores
4
12
Clinical Significance
Conservation
PhyloP100: 5.49
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 -11 ACMG points.
PM1
In a domain Cadherin 11 (size 105) in uniprot entity CAD23_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_022124.6
BP4
Computational evidence support a benign effect (MetaRNN=0.009121388).
BP6
Variant 10-71725515-G-A is Benign according to our data. Variant chr10-71725515-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45923.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00912 (1389/152356) while in subpopulation AFR AF= 0.0322 (1337/41576). AF 95% confidence interval is 0.0307. There are 29 homozygotes in gnomad4. There are 644 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 29 AD,AR,Digenic gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.3574G>A | p.Val1192Ile | missense_variant | 30/70 | ENST00000224721.12 | NP_071407.4 | |
CDH23 | NM_001171930.2 | c.3574G>A | p.Val1192Ile | missense_variant | 30/32 | NP_001165401.1 | ||
C10orf105 | NM_001168390.2 | c.-5-9173C>T | intron_variant | NP_001161862.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.3574G>A | p.Val1192Ile | missense_variant | 30/70 | 5 | NM_022124.6 | ENSP00000224721 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00906 AC: 1380AN: 152238Hom.: 29 Cov.: 33
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GnomAD3 exomes AF: 0.00210 AC: 513AN: 244778Hom.: 8 AF XY: 0.00155 AC XY: 207AN XY: 133240
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GnomAD4 exome AF: 0.000852 AC: 1245AN: 1460490Hom.: 22 Cov.: 32 AF XY: 0.000719 AC XY: 522AN XY: 726424
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GnomAD4 genome AF: 0.00912 AC: 1389AN: 152356Hom.: 29 Cov.: 33 AF XY: 0.00864 AC XY: 644AN XY: 74508
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 03, 2011 | Val1192Ile in exon 30 of CDH23: This variant is not expected to have clinical si gnificance because it has been identified in dbSNP in 4.2% (5/118) West African control chromosomes and 1.2% (11/917) mixed race control chromosomes (rs80028391 ). - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 11, 2016 | This 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. - |
Autosomal recessive nonsyndromic hearing loss 12 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This 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
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Dec 03, 2019 | - - |
Usher syndrome type 1D Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T;T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T;T
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;.;M;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
REVEL
Benign
Sift4G
Uncertain
D;D;.;D
Polyphen
0.14
.;.;B;.
Vest4
MVP
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at