Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_031885.5(BBS2):c.472-2A>G variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
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]
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.028624192 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 16-56510923-T-C is Pathogenic according to our data. Variant chr16-56510923-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 30550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
The BBS2 c.472-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant was reported in multiple individuals with Bardet-Biedl syndrome and is well known founder mutation in Hutterite population (Innes et al. 2010. PubMed ID: 20618352; Chong et al. 2012. PubMed ID: 22981120). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-56544835-T-C). Variants that disrupt the consensus splice acceptor site in BBS2 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Bardet-Biedl syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Invitae
Dec 25, 2023
This sequence change affects an acceptor splice site in intron 3 of the BBS2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 20618352, 22981120). It is commonly reported in individuals of Hutterite ancestry (PMID: 20618352, 22981120). ClinVar contains an entry for this variant (Variation ID: 30550). Studies have shown that disruption of this splice site results in skipping of exon 4 and exons 3-4, but is expected to preserve the integrity of the reading-frame (PMID: 20618352). For these reasons, this variant has been classified as Pathogenic. -