chr16-56484820-G-A
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_031885.5(BBS2):c.2107C>T(p.Arg703*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000929 in 1,613,992 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 (★★).
Frequency
Consequence
NM_031885.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BBS2 | ENST00000245157.11 | c.2107C>T | p.Arg703* | stop_gained | Exon 17 of 17 | 1 | NM_031885.5 | ENSP00000245157.5 | ||
ENSG00000288725 | ENST00000684388.1 | n.1027C>T | non_coding_transcript_exon_variant | Exon 8 of 14 | ENSP00000507647.1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152134Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251378Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135858
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461740Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7AN XY: 727186
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152252Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74436
ClinVar
Submissions by phenotype
Bardet-Biedl syndrome 2 Pathogenic:3
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Retinitis pigmentosa 74 Pathogenic:2
The BBS2 c.2107C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2. Based on this evidence we have classified this variant as Likely Pathogenic. -
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by less than 10%. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000496478 / PMID: 21344540). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Bardet-Biedl syndrome Pathogenic:2
This sequence change creates a premature translational stop signal (p.Arg703*) in the BBS2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 19 amino acid(s) of the BBS2 protein. This variant is present in population databases (rs567573386, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with BBS2-related disease (PMID: 21344540, 25999675; internal data). ClinVar contains an entry for this variant (Variation ID: 496478). For these reasons, this variant has been classified as Pathogenic. -
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Inborn genetic diseases Pathogenic:1
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BBS2-related disorder Pathogenic:1
The BBS2 c.2107C>T variant is predicted to result in premature protein termination (p.Arg703*). This variant has been reported in the homozygous state or with a second BBS2 variant in individuals with Bardet-Biedl syndrome (Deveault et al. 2011. PubMed ID: 21344540; Supplemental Table 1, Forsythe et al. 2016. PubMed ID: 27659767; Table S3, Fu et al. 2022. PubMed ID: 36307859) and reported in the homozygous state in an individual with retinitis pigmentosa (Xu et al. 2015. PubMed ID: 25999675). In addition, at PreventionGenetics, this variant has been seen in the homozygous or compound heterozygous states in individuals with features of Bardet-Biedl syndrome (Internal Data). This variant is reported in 0.027% of alleles in individuals of East Asian descent in a large population database. Nonsense variants in BBS2 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -
Retinal dystrophy Pathogenic:1
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Bardet-Biedl syndrome 2;C4225281:Retinitis pigmentosa 74 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at