10-71645934-TGGCCATCCCACTGGACTACGA-T
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM4PP3PP5
The NM_022124.6(CDH23):c.1246_1266del(p.Ala416_Glu422del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,200 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
CDH23
NM_022124.6 inframe_deletion
NM_022124.6 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.56
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_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_022124.6.
PP3
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
Variant 10-71645934-TGGCCATCCCACTGGACTACGA-T is Pathogenic according to our data. Variant chr10-71645934-TGGCCATCCCACTGGACTACGA-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45865.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.1246_1266del | p.Ala416_Glu422del | inframe_deletion | 13/70 | ENST00000224721.12 | |
CDH23 | NM_001171930.2 | c.1246_1266del | p.Ala416_Glu422del | inframe_deletion | 13/32 | ||
CDH23 | NM_001171931.2 | c.1246_1266del | p.Ala416_Glu422del | inframe_deletion | 13/26 | ||
CDH23 | NM_052836.4 | c.1246_1266del | p.Ala416_Glu422del | inframe_deletion | 13/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.1246_1266del | p.Ala416_Glu422del | inframe_deletion | 13/70 | 5 | NM_022124.6 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
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33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461200Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 726890
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GnomAD4 genome Cov.: 33
GnomAD4 genome
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33
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 08, 2013 | The Ala416_Glu422del variant in CDH23 has been identified in an individual with hearing loss by our laboratory who was compound heterozygous. It has not been i dentified in large and broad European American and African American populations by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). This variant causes an in-frame deletion of 7 amino acids conserved in mammals and ac ross evolutionarily distant species, which is likely to impact protein function. I n summary, this variant is likely pathogenic, though additional studies are r equired to fully establish its clinical significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 10, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 45865). This variant has not been reported in the literature in individuals affected with CDH23-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant, c.1246_1266del, is a complex sequence change that results in the deletion of 7 amino acid(s) in the CDH23 protein (p.Ala416_Glu422del). - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at