rs876657760
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_022124.6(CDH23):āc.9283A>Gā(p.Lys3095Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,453,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: not found (cov: 31)
Exomes š: 6.9e-7 ( 0 hom. )
Consequence
CDH23
NM_022124.6 missense
NM_022124.6 missense
Scores
7
12
Clinical Significance
Conservation
PhyloP100: 5.34
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 Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.34526807).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.9283A>G | p.Lys3095Glu | missense_variant | 65/70 | ENST00000224721.12 | |
LOC124902446 | XR_007062185.1 | n.1042T>C | non_coding_transcript_exon_variant | 1/2 | |||
CDH23 | NM_001171933.1 | c.2563A>G | p.Lys855Glu | missense_variant | 18/23 | ||
CDH23 | NM_001171934.1 | c.2563A>G | p.Lys855Glu | missense_variant | 18/22 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.9283A>G | p.Lys3095Glu | missense_variant | 65/70 | 5 | NM_022124.6 | P1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
GnomAD4 exome AF: 6.88e-7 AC: 1AN: 1453098Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 722212
GnomAD4 exome
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AC:
1
AN:
1453098
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
722212
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
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 19, 2015 | Variant classified as Uncertain Significance - Favor Benign. The p.Lys3095Glu va riant in CDH23 has not been previously reported in individuals with hearing loss and data from large population studies is insufficient to assess the frequency of this variant in the general population. Lysine (Lys) at position 3095 is not well conserved in evolutionarily distant species, with 5 fish species having a g lutamic acid (Glu) at this position. Additional computational prediction tools d o not provide strong support for or against an impact to the protein. In summary , the clinical significance of the p.Lys3095Glu variant is uncertain, the conser vation data suggests that it is more likely to be benign. - |
Usher syndrome type 1 Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 30, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T;.;.
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;L;.;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
.;.;.;N
REVEL
Benign
Sift
Benign
.;.;.;D
Sift4G
Uncertain
D;.;D;D
Polyphen
0.022
.;B;.;.
Vest4
MutPred
Loss of MoRF binding (P = 0.0024);Loss of MoRF binding (P = 0.0024);.;.;
MVP
MPC
0.25
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at