rs766873519
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_031885.5(BBS2):c.1207C>T(p.Arg403Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,614,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict 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. R403L) has been classified as Uncertain significance.
Frequency
Consequence
NM_031885.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BBS2 | NM_031885.5 | c.1207C>T | p.Arg403Cys | missense_variant | 10/17 | ENST00000245157.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BBS2 | ENST00000245157.11 | c.1207C>T | p.Arg403Cys | missense_variant | 10/17 | 1 | NM_031885.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 152016Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000676 AC: 17AN: 251492Hom.: 0 AF XY: 0.0000809 AC XY: 11AN XY: 135920
GnomAD4 exome AF: 0.0000493 AC: 72AN: 1461878Hom.: 0 Cov.: 33 AF XY: 0.0000468 AC XY: 34AN XY: 727234
GnomAD4 genome ? AF: 0.0000592 AC: 9AN: 152132Hom.: 0 Cov.: 31 AF XY: 0.0000672 AC XY: 5AN XY: 74372
ClinVar
Submissions by phenotype
Bardet-Biedl syndrome 2 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jan 27, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The BBS2 c.1207C>T (p.Arg403Cys) missense variant has been reported in one study in which it is found in two consanguineous families of Arab origin with Bardet-Biedl syndrome (Abu-Safieh et al. 2012). In one family, the single affected proband carried the variant in a homozygous state, while in the second family the variant was carried in a heterozygous state in three affected siblings, who also carried variants in three other BBS genes of unknown zygosity. The p.Arg403Cys variant was absent from 96 ethnically matched controls but is reported at a frequency of 0.00010 in the European (non-Finnish) population of the Exome Aggregation Consortium. The evidence for this variant is limited. The p.Arg403Cys variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for Bardet-Biedl syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Bardet-Biedl syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 403 of the BBS2 protein (p.Arg403Cys). This variant is present in population databases (rs766873519, gnomAD 0.02%). This missense change has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 22353939). ClinVar contains an entry for this variant (Variation ID: 319857). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BBS2 protein function with a negative predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 19, 2023 | Variant summary: BBS2 c.1207C>T (p.Arg403Cys) results in a non-conservative amino acid change located in the Ciliary BBSome complex subunit 2, C-terminal domain (IPR029333) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251492 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BBS2 causing Bardet-Biedl Syndrome (6.8e-05 vs 0.00098). c.1207C>T has been reported in the literature in at least one homozygous individuals affected with Bardet-Biedl Syndrome (e.g., Abu-Safieh_2012, Shaheen_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22353939, 27894351). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and all submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
BBS2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 27, 2023 | The BBS2 c.1207C>T variant is predicted to result in the amino acid substitution p.Arg403Cys. This variant has been reported in the homozygous state in one individual with Bardet-Biedl syndrome and in the heterozygous state in another individual who also carried other rare variants in Bardet-Biedl syndrome-related genes (Abu-Safieh et al. 2012. PubMed ID: 22353939). The authors did not provide any functional studies to help assess the pathogenicity of the c.1207C>T (p.Arg403Cys) variant. This variant is reported in 0.010% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at