rs121908175
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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):āc.72C>Gā(p.Tyr24Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000164 in 1,613,764 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 (ā ā ).
Frequency
Genomes: š 0.000033 ( 0 hom., cov: 32)
Exomes š: 0.00018 ( 0 hom. )
Consequence
BBS2
NM_031885.5 stop_gained
NM_031885.5 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 2.80
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 does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 59 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-56519791-G-C is Pathogenic according to our data. Variant chr16-56519791-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56519791-G-C is described in Lovd as [Likely_pathogenic]. Variant chr16-56519791-G-C is described in Lovd as [Pathogenic]. Variant chr16-56519791-G-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BBS2 | NM_031885.5 | c.72C>G | p.Tyr24Ter | stop_gained | 1/17 | ENST00000245157.11 | NP_114091.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BBS2 | ENST00000245157.11 | c.72C>G | p.Tyr24Ter | stop_gained | 1/17 | 1 | NM_031885.5 | ENSP00000245157 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000328 AC: 5AN: 152256Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000522 AC: 13AN: 249150Hom.: 0 AF XY: 0.0000518 AC XY: 7AN XY: 135194
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GnomAD4 exome AF: 0.000178 AC: 260AN: 1461390Hom.: 0 Cov.: 31 AF XY: 0.000173 AC XY: 126AN XY: 727038
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GnomAD4 genome AF: 0.0000328 AC: 5AN: 152374Hom.: 0 Cov.: 32 AF XY: 0.0000268 AC XY: 2AN XY: 74516
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Bardet-Biedl syndrome 2 Pathogenic:4
Likely pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jun 15, 2018 | The heterozygous p.Tyr24Ter variant was identified by our study in the compound heterozygous state, with a VUS, in one individual with Bardet-Biedl syndrome. This variant has been identified in <0.01% (12/125738) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121908175). Loss of function of the BBS2 gene is an established disease mechanism in autosomal recessive Bardet-Biedl syndrome 2, and this is a loss of function variant. In summary, although additional studies are required to fully establish its pathogenicity, this variant is likely pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Nov 03, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 19, 2024 | - - |
Bardet-Biedl syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 20, 2024 | This sequence change creates a premature translational stop signal (p.Tyr24*) 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 (rs121908175, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 11567139, 21344540). ClinVar contains an entry for this variant (Variation ID: 4570). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 10, 2017 | Variant summary: The BBS2 c.72C>G (p.Tyr24X) variant results in a premature termination codon, predicted to cause a truncated or absent BBS2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 7/116822 control chromosomes at a frequency of 0.0000599, which does not exceed the estimated maximal expected allele frequency of a pathogenic BBS2 variant (0.0008452). This variant has been reported in multiple BBS patients in homozygous or compound heterozygous state. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
BBS2-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 23, 2024 | The BBS2 c.72C>G variant is predicted to result in premature protein termination (p.Tyr24*). This variant has been reported in the homozygous or compound heterozygous states in individuals with Bardet-Biedl syndrome (Katsanis et al. 2001. PubMed ID: 11567139; Supplementary Data, Stone et al. 2017. PubMed ID: 28559085) and was identified in another individual with retinitis pigmentosa, although no second variant was described (Supplementary Data, Jespersgaard et al. 2019. PubMed ID: 30718709). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in BBS2 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Sep 18, 2017 | - - |
Bardet-Biedl syndrome 2;C4225281:Retinitis pigmentosa 74 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 07, 2021 | - - |
Retinitis pigmentosa Pathogenic:1
Pathogenic, no assertion criteria provided | research | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | Apr 01, 2018 | - - |
BARDET-BIEDL SYNDROME 2/6, DIGENIC Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 21, 2001 | - - |
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
MutationTaster
Benign
A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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