rs773862084

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_031885.5(BBS2):c.534+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000013 in 1,613,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

BBS2
NM_031885.5 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 7.18

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 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.029085873 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-56510858-C-A is Pathogenic according to our data. Variant chr16-56510858-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 553927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56510858-C-A is described in Lovd as [Pathogenic]. Variant chr16-56510858-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BBS2	NM_031885.5 link	c.534+1G>T		splice_donor_variant, intron_variant	Intron 4 of 16	ENST00000245157.11	NP_114091.4	Q9BXC9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BBS2	ENST00000245157.11 link	c.534+1G>T		splice_donor_variant, intron_variant	Intron 4 of 16	1	NM_031885.5	ENSP00000245157.5		Q9BXC9

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152174

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:

0.000962

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000994

AC:

AN:

251452

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00136

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461724

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727176

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000378

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000962

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bardet-Biedl syndrome 2

Pathogenic:7

Nov 03, 2021

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_031885.3(BBS2):c.534+1G>T is a canonical splice variant classified as pathogenic in the context of Bardet-Biedl syndrome, BBS2-related. c.534+1G>T has been observed in cases with relevant disease (PMID: 24280758, 33520300, 33777945). Functional assessments of this variant are not available in the literature. c.534+1G>T has been observed in population frequency databases (gnomAD: EAS 0.14%). In summary, NM_031885.3(BBS2):c.534+1G>T is a canonical splice variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Mar 16, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Department of Traditional Chinese Medicine, Fujian Provincial Hospital

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

This gene is a member of the Bardet-Biedl syndrome (BBS) gene family. Bardet-Biedl syndrome is a rare, autosomal recessive inherited, genetic syndrome, which involves multiple systems with diverse clinical manifestations, high disability rate and poor prognosis characterized by severe pigmentary retinopathy, obesity, polydactyly, renal malformation and cognitive disability. However, in this study, not only the proband who was homozygous mutation carriers showed typical retinitis pigmentation, polydactylism, obesity, bicornuate uterus, left renal dysplasia, hypogonadism and progressive renal dysfunction, but also those heterozygous mutation carriers in the family, manifests unequal development of both kidneys, gonadal hypoplasia and dilated cardiomyopathy, which were intermediate traits. Sequencing of the RT-PCR products from the proband’s blood sample reveals a 824-nucleotide (nt) insertion exists at the junction between exons 4 and 5 of the BBS2 cDNA. -

May 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.010%). Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000553927). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Department of Pediatrics, National Cheng-Kung University Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The c.534+1 G>T variant in BBS2 has been previously reported in BBS2 patients in several studies investigating syndromic ciliopathy. The variant was found in several of our patients with obesity, visual impairment, polydactyly, and renal disease, which are compatible with the BBS2 phenotype. Until now, there has not been an in vitro functional study to indicate the variant’s pathogenicity. However, it is a splice site mutation predicted to cause exon skipping, and multiple computational predictive software support its pathogenicity. In summary, the c.534+1 G>T variant in BBS2 meets the criteria of ACMG/AMP guidelines to be classified as pathogenic based on the clinical information. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 05, 2025

SingHealth Duke-NUS Institute of Precision Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant is predicted to cause nonsense-mediated decay in a gene where LOF is a known cause of pathogenicity (PVS1). Homozygous allele count in gnomAD genomes or exomes are less than 0 (PM2). -

Bardet-Biedl syndrome 2;C4225281:Retinitis pigmentosa 74

Pathogenic:2

Mar 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1_Strong+PM2_Supporting+PM3_Supporting+PP1_Strong+PP4 -

not provided

Pathogenic:1

Aug 25, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy

Pathogenic:1

Feb 20, 2018

Blueprint Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bardet-Biedl syndrome

Pathogenic:1

Jun 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 4 of the BBS2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BBS2 are known to be pathogenic (PMID: 11285252, 20177705, 24608809, 26518167). This variant is present in population databases (rs773862084, gnomAD 0.1%). Disruption of this splice site has been observed in individual(s) with Bardet-Biedl syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 553927). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.99

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.99

Position offset: 1

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