chr10-71707053-C-T
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_022124.6(CDH23):c.3106+4C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,445,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
CDH23
NM_022124.6 splice_donor_region, intron
NM_022124.6 splice_donor_region, intron
Scores
1
12
Clinical Significance
Conservation
PhyloP100: -0.788
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 -2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.058864295).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.3106+4C>T | splice_donor_region_variant, intron_variant | ENST00000224721.12 | |||
CDH23 | NM_001171931.2 | c.3110C>T | p.Ala1037Val | missense_variant | 26/26 | ||
CDH23 | NM_001171930.2 | c.3106+4C>T | splice_donor_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.3106+4C>T | splice_donor_region_variant, intron_variant | 5 | NM_022124.6 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.00000138 AC: 2AN: 1445868Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1AN XY: 717732
GnomAD4 exome
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2
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1445868
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31
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1
AN XY:
717732
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
Bravo
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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 | Aug 28, 2014 | Variant classified as Uncertain Significance - Favor Benign. The Ala1037Val vari ant in CDH23 (NM_01171391.1) has not been previously reported in individuals wit h hearing loss and was absent from large population studies. The alanine (Ala) a t position 1037 is not conserved in mammals or evolutionary distant species, rai sing the possibility that a change at this position may be tolerated. Additional computational prediction tools suggest the Ala1037Val variant may not impact th e protein, though this information is not predictive enough to rule out pathogen icity. Note that in an alternate transcript of CDH23, the variant occurs at the +4 splice site position (c.3106+4C>T in NM_022124.5). However, this variant does not affect the invariant +1/+2 positions of the splice site consensus sequence and computational tools do not predict an impact to splicing. In summary, while the clinical significance of the Ala1037Val variant is uncertain, these data sug gest that 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
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationTaster
Benign
N;N
REVEL
Benign
Sift4G
Benign
T
Vest4
MVP
ClinPred
D
GERP RS
Splicing
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Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at