rs121908177

Positions:

chr16-56502790-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_031885.5(BBS2):c.823C>T(p.Arg275Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000258 in 1,613,980 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R275R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

BBS2
NM_031885.5 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 6.72

Variant links:

Genes affected

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]

BBS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-56502790-G-A is Pathogenic according to our data. Variant chr16-56502790-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56502790-G-A is described in Lovd as [Pathogenic]. Variant chr16-56502790-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS2	NM_031885.5 linkuse as main transcript	c.823C>T	p.Arg275Ter	stop_gained	8/17	ENST00000245157.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS2	ENST00000245157.11 linkuse as main transcript	c.823C>T	p.Arg275Ter	stop_gained	8/17	1	NM_031885.5	P1

Frequencies

GnomAD3 genomes

AF:

0.0000921

AC:

AN:

151978

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000191

AC:

AN:

251356

Hom.:

AF XY:

0.000184

AC XY:

AN XY:

135860

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:

0.0000327

Gnomad FIN exome

AF:

0.000647

Gnomad NFE exome

AF:

0.000273

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000275

AC:

402

AN:

1461884

Hom.:

Cov.:

AF XY:

0.000260

AC XY:

189

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000824

Gnomad4 NFE exome

AF:

0.000292

Gnomad4 OTH exome

AF:

0.000497

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000212

Hom.:

Bravo

AF:

0.0000642

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000214

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bardet-Biedl syndrome 2

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 25, 2018	Variant summary: BBS2 c.823C>T (p.Arg275X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One truncation downstream of this position has been classified as pathogenic by our laboratory (eg. c.1864C>T, p.Arg622X). The variant allele was found at a frequency of 0.0002 in 277510 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in BBS2 causing Bardet-Biedl Syndrome (0.0002 vs 0.00085), allowing no conclusion about variant significance. The variant, c.823C>T, has been reported in the literature in multiple individuals affected with Bardet-Biedl Syndrome (Katsanis_2001, Nishimura_2001, Badano_2003). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 21, 2001	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The BBS2 c.823C>T (p.Arg275Ter) variant is a stop-gained variant that is predicted to result in premature termination of the protein. The p.Arg275Ter variant has been reported in at least five studies in which it is found in at least nine patients with Bardet-Biedl syndrome including in six from four independent families in a homozygous state, in one in a compound heterozygous state, in one in a heterozygous state with a second missense variant where phase is unknown, and in one in a heterozygous state with two additional variants in the BBS1 gene (Katsanis et al. 2001; Nishimura et al. 2001; Badano et al. 2003; Chen et al. 2011; Janssen et al. 2011). The variant is also found in a heterozygous state in at least four unaffected family members (Katsanis et al. 2001; Badano et al. 2003). The p.Arg275Ter variant was absent from at least 312 control chromosomes but is reported at a frequency of 0.00076 in the European (Finnish) population of the Exome Aggregation Consortium. Based on the evidence and potential impact of stop-gained variants, the p.Arg275Ter variant is classified as 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	Myriad Genetics, Inc.	Dec 20, 2019	NM_031885.3(BBS2):c.823C>T(R275) is classified as pathogenic in the context of BBS2-related Bardet-Biedl Syndrome. Sources cited for classification include the following: PMID 11567139 and 11285252. Classification of NM_031885.3(BBS2):c.823C>T(R275) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2021	Identified in the homozygous state or with a pathogenic variant on the opposite allele in multiple unrelated patients with Bardet-Biedl syndrome referred for genetic testing at GeneDx and in the published literature (Katsanis et al., 2001; Bandano et al., 2003; Janssen et al., 2011; Olson et al., 2018); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 11285252, 11567139, 25525159, 28502102, 28559085, 21642631, 12837689, 21052717, 30293640, 28387813, 27535533, 31980526, 31589614) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 11, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2019	- -

Bardet-Biedl syndrome 2;C4225281:Retinitis pigmentosa 74

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 07, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Nov 30, 2020	- -

Retinitis pigmentosa 74

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Jul 25, 2021

- -

BBS2-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 02, 2024

The BBS2 c.823C>T variant is predicted to result in premature protein termination (p.Arg275*). This variant has been reported in the homozygous or compound heterozygous state in many individuals with Bardet-Biedl syndrome (see for example, Katsanis et al. 2001. PubMed ID: 11567139; Lei et al. 2017. PubMed ID: 28387813; Álvarez-Satta et al. 2017. PubMed ID: 28502102; Meyer et al. 2022. PubMed ID: 35112343). This variant is reported in 0.064% of alleles in individuals of European (Finnish) descent in gnomAD. Nonsense variants in BBS2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jan 05, 2019

- -

Bardet-Biedl syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

This sequence change creates a premature translational stop signal (p.Arg275*) in the BBS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BBS2 are known to be pathogenic (PMID: 11285252, 20177705, 24608809, 26518167). This variant is present in population databases (rs121908177, gnomAD 0.07%). This premature translational stop signal has been observed in individuals with Bardet-Biedl syndrome (PMID: 11285252, 11567139, 12837689, 21052717, 21642631). ClinVar contains an entry for this variant (Variation ID: 4572). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.98

MutationTaster

Benign

1.0

A;A

Vest4

0.81

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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