rs752202089
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_152618.3(BBS12):c.2023C>T(p.Arg675Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000436 in 1,606,830 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
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
BBS12
NM_152618.3 stop_gained
NM_152618.3 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.94
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 14 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 7 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 4-122743915-C-T is Pathogenic according to our data. Variant chr4-122743915-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 347505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-122743915-C-T is described in Lovd as [Pathogenic]. Variant chr4-122743915-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BBS12 | NM_152618.3 | c.2023C>T | p.Arg675Ter | stop_gained | 2/2 | ENST00000314218.8 | |
BBS12 | NM_001178007.2 | c.2023C>T | p.Arg675Ter | stop_gained | 3/3 | ||
BBS12 | XM_011531680.3 | c.2023C>T | p.Arg675Ter | stop_gained | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BBS12 | ENST00000314218.8 | c.2023C>T | p.Arg675Ter | stop_gained | 2/2 | 1 | NM_152618.3 | P1 | |
BBS12 | ENST00000542236.5 | c.2023C>T | p.Arg675Ter | stop_gained | 3/3 | 2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152120Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000812 AC: 2AN: 246292Hom.: 0 AF XY: 0.0000150 AC XY: 2AN XY: 133052
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GnomAD4 exome AF: 0.00000412 AC: 6AN: 1454710Hom.: 0 Cov.: 32 AF XY: 0.00000277 AC XY: 2AN XY: 722966
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Bardet-Biedl syndrome 12 Pathogenic:6
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | The BBS12 c.2023C>T (p.Arg675Ter) stop-gained variant has been reported in two studies in a total of three individuals, either with Bardet-Biedl syndrome (BBS) or suspected to have BBS, in a compound heterozygous state (Dulfer et al. 2010; Chen et al. 2011). Of these individuals, two were siblings who also had a heterozygous frameshift variant in the BBS10 gene. In this family, the father was heterozygous for the BBS12 p.Arg675Ter variant and the mother was heterozygous for the other variants. The other individual who had the p.Arg675Ter variant in a compound heterozygous state also had a heterozygous missense variant in the BBS1 gene. The p.Arg675Ter variant was absent from 288 controls but is reported at a frequency of 0.00002 in the European (non-Finnish) population of the Exome Aggregation Consortium, however this is based on one allele in a region of good sequence coverage so the variant is presumed to be rare. Based on the evidence and due to potential impact of stop-gained variants, the p.Arg675Ter variant is classified as likely pathogenic for Bardet-Biedl syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The stop gain variant c.2023C>T (p.Arg675Ter) in the BBS12 gene has been reported previously in a compound heterozygous state in patients affected with Bardet–Biedl Syndrome. Two of the patients also had a heterozygous frameshift variant in the BBS10 gene along with the BBS12 variants (Dulfer E. et al., 2010). This variant is reported with the allele frequency (0.0008%) in the gnomAD Exomes and novel in 1000 genome database. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 08, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Oct 18, 2017 | - - |
not provided Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2016 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Bardet-Biedl syndrome Pathogenic:2
Pathogenic, no assertion criteria provided | provider interpretation | Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University | Sep 15, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change creates a premature translational stop signal (p.Arg675*) in the BBS12 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 36 amino acid(s) of the BBS12 protein. This variant is present in population databases (rs752202089, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 20827784, 21642631). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 347505). For these reasons, this variant has been classified as Pathogenic. - |
BBS12-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 12, 2023 | The BBS12 c.2023C>T variant is predicted to result in premature protein termination (p.Arg675*). This variant has been reported to be causative for Bardet-Biedl syndrome (Dulfer. 2010. PubMed ID: 20827784; Mary et al. 2019. PubMed ID: 30614526). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-123665070-C-T). Nonsense variants in BBS12 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D
Vest4
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