Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_031885.5(BBS2):c.471G>A(p.Thr157=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
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 Likely_pathogenic. Variant got 7 ACMG points.
PM2
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PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP3
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PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
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PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 16-56511159-C-T is Pathogenic according to our data. Variant chr16-56511159-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 551904.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2}. Variant chr16-56511159-C-T is described in Lovd as [Pathogenic].
Uncertain significance, criteria provided, single submitter
clinical testing
Neuberg Centre For Genomic Medicine, NCGM
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The synonymous variant p.T157= in BBS2 (NM_031885.5) has been previously reported in an individual with retinis pigmentosa (Wang F et al). The variant has been submitted to ClinVar as Uncertain significance.The p.T157= variant is observed in 1/30,612 (0.0033%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The variant affects an invariant splice nucleotide and hence may affect splicing. The p.T157= variant is predicted to disrupt splicing by 3 of 4 splice site algorithms. Since the variant is a synonymous change it is classified as Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter
clinical testing
Baylor Genetics
Mar 27, 2024
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Uncertain significance, criteria provided, single submitter
clinical testing
Counsyl
May 16, 2017
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Bardet-Biedl syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter
clinical testing
Invitae
Mar 14, 2023
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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 551904). This variant has been observed in individuals with Bardet-Biedl syndrome and/or retinitis pigmentosa (PMID: 24154662, 29588463; Invitae). This variant is present in population databases (rs749983428, gnomAD 0.003%). This sequence change affects codon 157 of the BBS2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the BBS2 protein. This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon. -