rs201876362
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_022124.6(CDH23):āc.5831T>Cā(p.Leu1944Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000488 in 1,576,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 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: š 0.00024 ( 0 hom., cov: 33)
Exomes š: 0.000028 ( 0 hom. )
Consequence
CDH23
NM_022124.6 missense
NM_022124.6 missense
Scores
3
12
Clinical Significance
Conservation
PhyloP100: 5.88
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 Likely_benign. Variant got -5 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.040349364).
BP6
?
Variant 10-71788950-T-C is Benign according to our data. Variant chr10-71788950-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45993.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.5831T>C | p.Leu1944Ser | missense_variant | 45/70 | ENST00000224721.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.5831T>C | p.Leu1944Ser | missense_variant | 45/70 | 5 | NM_022124.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000243 AC: 37AN: 152146Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000762 AC: 19AN: 249210Hom.: 0 AF XY: 0.0000592 AC XY: 8AN XY: 135214
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GnomAD4 exome AF: 0.0000281 AC: 40AN: 1424676Hom.: 0 Cov.: 26 AF XY: 0.0000281 AC XY: 20AN XY: 711268
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GnomAD4 genome ? AF: 0.000243 AC: 37AN: 152146Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14AN XY: 74318
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 02, 2016 | The p.Leu1944Ser variant in CDH23 has been reported in 1 individual with profoun d sensorineural hearing loss who was heterozygous for two pathogenic variants in another gene that likely explained the hearing loss (LMM data). This variant ha s been identified in 0.1% (9/9754) of African chromosomes by the Exome Aggregati on Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201876362). Althoug h this variant has been seen in the general population, its frequency is not hig h enough to rule out a pathogenic role. Computational prediction tools and conse rvation analyses do not provide strong support for or against an impact to the p rotein. In summary, the clinical significance of the p.Leu1944Ser variant is unc ertain - |
Usher syndrome type 1 Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 28, 2019 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 31, 2023 | - - |
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
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationTaster
Benign
N
PrimateAI
Benign
T
Sift4G
Uncertain
D;.
Polyphen
0.28
.;B
Vest4
MVP
ClinPred
T
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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