rs201196733
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_031885.5(BBS2):c.1864C>T(p.Arg622*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000273 in 1,613,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000029 ( 0 hom. )
Consequence
BBS2
NM_031885.5 stop_gained
NM_031885.5 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.27
Genes affected
BBS2 (HGNC:967): (Bardet-Biedl syndrome 2) This gene is a member of the Bardet-Biedl syndrome (BBS) gene family. Bardet-Biedl syndrome is an autosomal recessive disorder characterized by severe pigmentary retinopathy, obesity, polydactyly, renal malformation and cognitive disability. The proteins encoded by BBS gene family members are structurally diverse and the similar phenotypes exhibited by mutations in BBS gene family members is likely due to their shared roles in cilia formation and function. Many BBS proteins localize to the basal bodies, ciliary axonemes, and pericentriolar regions of cells. BBS proteins may also be involved in intracellular trafficking via microtubule-related transport. The protein encoded by this gene forms a multiprotein BBSome complex with seven other BBS proteins.[provided by RefSeq, Oct 2014]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-56497013-G-A is Pathogenic according to our data. Variant chr16-56497013-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 284737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56497013-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BBS2 | NM_031885.5 | c.1864C>T | p.Arg622* | stop_gained | 15/17 | ENST00000245157.11 | NP_114091.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BBS2 | ENST00000245157.11 | c.1864C>T | p.Arg622* | stop_gained | 15/17 | 1 | NM_031885.5 | ENSP00000245157.5 | ||
ENSG00000288725 | ENST00000684388.1 | n.784C>T | non_coding_transcript_exon_variant | 6/14 | ENSP00000507647.1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152036Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251430Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135878
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GnomAD4 exome AF: 0.0000287 AC: 42AN: 1461804Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 20AN XY: 727198
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GnomAD4 genome AF: 0.0000132 AC: 2AN: 152036Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74246
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Bardet-Biedl syndrome 2 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Bardet-Biedl syndrome 2 (MIM#615981) and retinitis pigmentosa 74 (MIM#616562). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 7 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (Decipher; PMID: 31283077). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic or pathogenic by clinical diagnostic laboratories and has been reported as compound heterozygous in individuals with Bardet-Biedl syndrome 2 (ClinVar; PMIDs: 21344540, 26078953). This variant is also compound heterozygous in one individual with chronic kidney disease without a specific diagnosis and heterozygous in an individual with inherited retinal disease (PMIDs: 33226606, 31429209). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Nov 02, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 20, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 02, 2018 | Variant summary: BBS2 c.1864C>T (p.Arg622X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation downstream of this position has been classified as likely pathogenic by our laboratory, c.2107C>T (p.Arg703X). The variant has been observed with an allele frequency of 2.8e-05 in 246196 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BBS2 causing Bardet-Biedl Syndrome (2.8e-05 vs. 8.5e-04), allowing no conclusion about variant significance. The variant, c.1864C>T, has been reported in the literature in individuals affected with Bardet-Biedl Syndrome (Bee 2015, Deveault 2011). 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. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) have classified the variant as "likely pathogenic/pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jan 05, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 08, 2015 | - - |
Bardet-Biedl syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 02, 2023 | This sequence change creates a premature translational stop signal (p.Arg622*) in the BBS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BBS2 are known to be pathogenic (PMID: 11285252, 20177705, 24608809, 26518167). This variant is present in population databases (rs201196733, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with Bardet-Biedl syndrome (PMID: 21344540, 26078953). ClinVar contains an entry for this variant (Variation ID: 284737). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Bardet-Biedl syndrome 2;C4225281:Retinitis pigmentosa 74 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 09, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
Vest4
0.90, 0.98
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at