rs752202089

Positions:

chr4-122743915-C-T

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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 4.94

Variant links:

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]

BBS12 links:

Genome browser will be placed here

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 4 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	Protein
BBS12	NM_152618.3 linkuse as main transcript	c.2023C>T	p.Arg675Ter	stop_gained	2/2	ENST00000314218.8	NP_689831.2
BBS12	NM_001178007.2 linkuse as main transcript	c.2023C>T	p.Arg675Ter	stop_gained	3/3		NP_001171478.1
BBS12	XM_011531680.3 linkuse as main transcript	c.2023C>T	p.Arg675Ter	stop_gained	2/2		XP_011529982.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BBS12	ENST00000314218.8 linkuse as main transcript	c.2023C>T	p.Arg675Ter	stop_gained	2/2	1	NM_152618.3	ENSP00000319062	P1
BBS12	ENST00000542236.5 linkuse as main transcript	c.2023C>T	p.Arg675Ter	stop_gained	3/3	2		ENSP00000438273	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.00000812

AC:

AN:

246292

Hom.:

AF XY:

0.0000150

AC XY:

AN XY:

133052

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000412

AC:

AN:

1454710

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

722966

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000451

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.0000308

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

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

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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. -
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	- -
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, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 08, 2024	- -

not provided

Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Kariminejad - Najmabadi Pathology & Genetics Center	Jul 10, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Bardet-Biedl syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -
Pathogenic, no assertion criteria provided	provider interpretation	Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University	Sep 15, 2018	- -

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.61

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.93

MutationTaster

Benign

1.0

D;D

Vest4

0.24

GERP RS

5.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over