rs762047808
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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.1780C>T(p.Arg594Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,613,124 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 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )
Consequence
BBS2
NM_031885.5 stop_gained
NM_031885.5 stop_gained
Scores
2
3
2
Clinical Significance
Conservation
PhyloP100: 3.20
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 16-56497760-G-A is Pathogenic according to our data. Variant chr16-56497760-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 550489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56497760-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| BBS2 | NM_031885.5 | c.1780C>T | p.Arg594Ter | stop_gained | 14/17 | ENST00000245157.11 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BBS2 | ENST00000245157.11 | c.1780C>T | p.Arg594Ter | stop_gained | 14/17 | 1 | NM_031885.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000198 AC: 3AN: 151842Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251104Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135728
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GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461282Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16AN XY: 726960
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GnomAD4 genome ? AF: 0.0000198 AC: 3AN: 151842Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 74128
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Bardet-Biedl syndrome 2 Pathogenic:4
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 05, 2021 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 26, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 21, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins-Biomnis | Nov 24, 2022 | - - |
Bardet-Biedl syndrome 2;C4225281:Retinitis pigmentosa 74 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 16, 2021 | - - |
Bardet-Biedl syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 02, 2023 | This sequence change creates a premature translational stop signal (p.Arg594*) 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 (rs762047808, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 27032803). ClinVar contains an entry for this variant (Variation ID: 550489). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;D
Vest4
0.95
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