rs121908179

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_031885.5(BBS2):c.311A>C(p.Asp104Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,614,032 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

BBS2
NM_031885.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 7.86

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 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.958

PP5

Variant 16-56514487-T-G is Pathogenic according to our data. Variant chr16-56514487-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 4577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56514487-T-G is described in Lovd as [Pathogenic]. Variant chr16-56514487-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BBS2	NM_031885.5 link	c.311A>C	p.Asp104Ala	missense_variant	Exon 2 of 17	ENST00000245157.11	NP_114091.4	Q9BXC9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BBS2	ENST00000245157.11 link	c.311A>C	p.Asp104Ala	missense_variant	Exon 2 of 17	1	NM_031885.5	ENSP00000245157.5		Q9BXC9

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000437

AC:

AN:

251464

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000287

AC:

AN:

1461854

Hom.:

Cov.:

AF XY:

0.0000371

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000222

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bardet-Biedl syndrome

Pathogenic:3

Jun 30, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The c.311A>C (p.D104A) in BBS2 gene is a missense change that alters a conserved nucleotide and 5/5 in silico tools predict deleterious outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.00005 exclusively in individuals of European descent (0.000075). This frequency does not exceed the maximal expected allele frequency for a pathogenic variant in BBS2 gene (0.0008). Fedick (2014) reports the carrier frequency of 0.473% (0.0071%) for Jewish population. The variant of interest has been reported in multiple BBS pts in compound heterozygous state and in 2 homozygous individuals presented with nonsyndromic autosomal recessive RP (Shevach, 2014). Taking together, the variant was classified as Pathogenic. -

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 104 of the BBS2 protein (p.Asp104Ala). This variant is present in population databases (rs121908179, gnomAD 0.1%). This missense change has been observed in individuals with Bardet-Biedl syndrome (PMID: 11567139, 21344540, 21642631, 23829372). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4577). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt BBS2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects BBS2 function (PMID: 20498079). For these reasons, this variant has been classified as Pathogenic. -

Apr 26, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Retinitis pigmentosa 74

Pathogenic:2

Mar 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 04, 2022

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The heterozygous p.Asp104Ala variant in BBS2 was identified by our study, along with another pathogenic variant, in 1 individual with retinitis pigmentosa 74. The variant has been reported in at least 4 Ashkenazi Jewish individuals with retinitis pigmentosa 74 (PMID: 23829372), and has been identified in 0.1% (10/10080) of Ashkenazi Jewish and 0.0009% (1/113746) of European non-Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs121908179). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 4577) as pathogenic by Integrated Genetics/Laboratory Corporation of America, Invitae, OMIM, and Sharon lab, Hadassah-Hebrew University Medical Center, and as likely pathogenic by Counsyl and Fulgent Genetics. Animal models in zebrafish have shown that this variant causes retinitis pigmentosa 74 (PMID: 20498079). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in 2 affected homozygotes, in combination with a reported pathogenic variant, and in 4 individuals with retinitis pigmentosa 74 increases the likelihood that the p.Asp104Ala variant is pathogenic (VariationID: 4578; PMID: 23829372). In summary, this variant meets criteria to be classified as pathogenic for retinitis pigmentosa 74 in an autosomal recessive manner based on its disease-causing effect in an animal model, and its homozygous occurrence and occurrence with other pathogenic variants in trans in affected individuals. ACMG/AMP Criteria applied: PS3, PM3_strong, PP3 (Richards 2015). -

Bardet-Biedl syndrome 2

Pathogenic:2

Jan 30, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 26, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bardet-Biedl syndrome 2;C4225281:Retinitis pigmentosa 74

Pathogenic:2

Jan 31, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 23, 2022

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa

Pathogenic:2

Apr 01, 2021

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Asp104Ala variant in BBS2 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PS3, PM2, PM3, PP1, PP3. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. -

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Bardet-biedl syndrome 1/2, digenic

Pathogenic:1

Mar 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:1

Dec 18, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect suggestive of a dominant negative mechanism (PMID: 20498079); This variant is associated with the following publications: (PMID: 25541840, 19402160, 31964843, 35112343, 11567139, 23829372, 31456290, 32037395, 20498079) -

BBS2-related disorder

Pathogenic:1

Aug 20, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BBS2 c.311A>C variant is predicted to result in the amino acid substitution p.Asp104Ala. This sequence variant has been reported in multiple individuals with Bardet-Biedl syndrome 2, retinitis pigmentosa 74, and cone-rod dystrophy (Katsanis et al. 2001. PubMed ID: 11567139; Consugar et al 2015. PubMed ID: 25412400; Shevach et al 2015. PubMed ID: 25541840). This variant is reported in 0.099% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-56548399-T-G). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

D;.

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.95

D;.

M_CAP

Benign

0.040

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Uncertain

0.47

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-5.7

D;D

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.027

D;D

Vest4

0.93

MutPred

0.94

Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);

MVP

0.89

MPC

1.0

ClinPred

0.95

GERP RS

5.4

gMVP

0.90

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