chr15-78105319-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP5BP4
The NM_006383.4(CIB2):c.556C>T(p.Arg186Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 1,614,024 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R186Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_006383.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CIB2 | NM_006383.4 | c.556C>T | p.Arg186Trp | missense_variant | 6/6 | ENST00000258930.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CIB2 | ENST00000258930.8 | c.556C>T | p.Arg186Trp | missense_variant | 6/6 | 1 | NM_006383.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000204 AC: 31AN: 152134Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000319 AC: 8AN: 251128Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135756
GnomAD4 exome AF: 0.0000376 AC: 55AN: 1461772Hom.: 0 Cov.: 30 AF XY: 0.0000330 AC XY: 24AN XY: 727188
GnomAD4 genome ? AF: 0.000204 AC: 31AN: 152252Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16AN XY: 74426
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 25, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 186 of the CIB2 protein (p.Arg186Trp). This variant is present in population databases (rs370359511, gnomAD 0.05%). This missense change has been observed in individuals with non-syndromic sensorineural deafness (PMID: 26426422, 29112224, 34837038). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 499480). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CIB2 function (PMID: 26426422, 28663585). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 03, 2022 | Published functional studies suggest the R186W variant results in the loss of calcium sequestering ability relative to wild-type (Patel et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28663585, 30174586, 26426422, 29112224, 35440622) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 20, 2017 | - - |
Autosomal recessive nonsyndromic hearing loss 48 Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Laboratory of Prof. Karen Avraham, Tel Aviv University | Jan 31, 2021 | - - |
Usher syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 21, 2022 | Variant summary: CIB2 c.556C>T (p.Arg186Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251128 control chromosomes. c.556C>T has been reported in the literature as a homozygous genotype in two affected probands each from at-least two distinct families (Carribean and Yoruba Nigerian) with features of Non-syndromic hearing loss (NSHL) and secondary citations by others (example, Patel_2015, Delio_2015, Booth_2019, Adeyemo_2022). Biallelic loss of function variants in CIB2 have been reported to cause autosomal recessive non-syndromic hearing loss (ARNSHL) and not Usher syndrome (USH) (Booth_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no conclusive experimental evidence demonstrating an impact on protein function has been reported, although one study reported p.Arg186Trp mutation affects the calcium binding affinity of CIB2 but did not alter the interactions of CIB2 with Whirlin, nor its targeting to the tips of hair cell stereocilia (Patel_2015). Another study reported this variant as not having notable changes in CIB2 intracellular localization in CHO-K1 cells and no effect on interactions with TMC1 in vitro (Giese_2017). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=3, P/LP, n=2). Some submitters cite overlapping but not identical evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Childhood onset hearing loss Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | National Institute on Deafness and Communication Disorders, National Institutes of Health | Jul 08, 2021 | PS3_supporting, PM1, PM2_supporting, PM3_supporting, PP1_moderate / Modifications from PMID: 30311386 for classification: The genetic causes of hearing loss have not yet been well characterized in the Yoruba population, and the information regarding variant MAF in this population is still limited, so we did not exclude any variant based on their "high" MAF. PP3 criteria was applied even if the REVEL score was below 0.7, if at least two of the pathogenicity prediction algorithms used predicted that the variant was damaging or likely damaging. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 22, 2019 | Variant classified as Uncertain Significance - Favor Pathogenic. The p. Arg186Trp variant in CIB2 has been previously reported in the homozygous state in 1 Caribbean Hispanic individual with hearing loss and segregated with disease in 1 affected sibling, also homozygous for the variant (Patel 2015). This variant has been identified in 0.05% (13/24914) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is present in ClinVar (Variation ID 499480). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied: PM2_Supporting, PP1, PP3, PM3_Supporting. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at