rs1057517193
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_152618.3(BBS12):βc.1082delβ(p.Gly361ValfsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,614,104 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ).
Frequency
Genomes: π 0.000013 ( 0 hom., cov: 33)
Exomes π: 0.000012 ( 0 hom. )
Consequence
BBS12
NM_152618.3 frameshift
NM_152618.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.291
Genes affected
BBS12 (HGNC:26648): (Bardet-Biedl syndrome 12) The protein encoded by this gene is part of a complex that is involved in membrane trafficking. The encoded protein is a molecular chaperone that aids in protein folding upon ATP hydrolysis. This protein also plays a role in adipocyte differentiation. Defects in this gene are a cause of Bardet-Biedl syndrome type 12. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, May 2010]
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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 is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 66 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 4-122742971-AG-A is Pathogenic according to our data. Variant chr4-122742971-AG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BBS12 | NM_152618.3 | c.1082del | p.Gly361ValfsTer22 | frameshift_variant | 2/2 | ENST00000314218.8 | |
BBS12 | NM_001178007.2 | c.1082del | p.Gly361ValfsTer22 | frameshift_variant | 3/3 | ||
BBS12 | XM_011531680.3 | c.1082del | p.Gly361ValfsTer22 | frameshift_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BBS12 | ENST00000314218.8 | c.1082del | p.Gly361ValfsTer22 | frameshift_variant | 2/2 | 1 | NM_152618.3 | P1 | |
BBS12 | ENST00000542236.5 | c.1082del | p.Gly361ValfsTer22 | frameshift_variant | 3/3 | 2 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152244Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251364Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135874
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GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461860Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 727230
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152244Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74376
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Bardet-Biedl syndrome 12 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Sep 08, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 25, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 07, 2023 | - - |
Bardet-Biedl syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | This sequence change creates a premature translational stop signal (p.Gly361Valfs*22) in the BBS12 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 350 amino acid(s) of the BBS12 protein. This variant is present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 24611592). ClinVar contains an entry for this variant (Variation ID: 371339). This variant disrupts a region of the BBS12 protein in which other variant(s) (p.Arg675*) have been determined to be pathogenic (PMID: 20827784, 21642631). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at