rs766873519

Positions:

chr16-56501371-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_031885.5(BBS2):c.1207C>T(p.Arg403Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,614,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

BBS2
NM_031885.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:7

Conservation

PhyloP100: 0.588

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:

ENSG00000288725 (HGNC:):

ENSG00000288725 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14493501).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BBS2	NM_031885.5 link	c.1207C>T	p.Arg403Cys	missense_variant	10/17	ENST00000245157.11	NP_114091.4	Q9BXC9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BBS2	ENST00000245157.11 link	c.1207C>T	p.Arg403Cys	missense_variant	10/17	1	NM_031885.5	ENSP00000245157.5		Q9BXC9
ENSG00000288725	ENST00000684388.1 link	n.127C>T		non_coding_transcript_exon_variant	1/14			ENSP00000507647.1		A0A804HJU2

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000676

AC:

AN:

251492

Hom.:

AF XY:

0.0000809

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000493

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000522

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000818

Hom.:

Bravo

AF:

0.0000945

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Bardet-Biedl syndrome 2

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 27, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The BBS2 c.1207C>T (p.Arg403Cys) missense variant has been reported in one study in which it is found in two consanguineous families of Arab origin with Bardet-Biedl syndrome (Abu-Safieh et al. 2012). In one family, the single affected proband carried the variant in a homozygous state, while in the second family the variant was carried in a heterozygous state in three affected siblings, who also carried variants in three other BBS genes of unknown zygosity. The p.Arg403Cys variant was absent from 96 ethnically matched controls but is reported at a frequency of 0.00010 in the European (non-Finnish) population of the Exome Aggregation Consortium. The evidence for this variant is limited. The p.Arg403Cys variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for Bardet-Biedl syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 25, 2024	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27894351, 22353939) -

Bardet-Biedl syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 12, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 403 of the BBS2 protein (p.Arg403Cys). This variant is present in population databases (rs766873519, gnomAD 0.02%). This missense change has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 22353939). ClinVar contains an entry for this variant (Variation ID: 319857). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BBS2 protein function with a negative predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 19, 2023

Variant summary: BBS2 c.1207C>T (p.Arg403Cys) results in a non-conservative amino acid change located in the Ciliary BBSome complex subunit 2, C-terminal domain (IPR029333) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251492 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BBS2 causing Bardet-Biedl Syndrome (6.8e-05 vs 0.00098). c.1207C>T has been reported in the literature in at least one homozygous individuals affected with Bardet-Biedl Syndrome (e.g., Abu-Safieh_2012, Shaheen_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22353939, 27894351). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and all submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

BBS2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 17, 2024

The BBS2 c.1207C>T variant is predicted to result in the amino acid substitution p.Arg403Cys. This variant has been reported in the homozygous state in one individual with Bardet-Biedl syndrome and in the heterozygous state in another individual who also carried other rare variants in Bardet-Biedl syndrome-related genes (Abu-Safieh et al. 2012. PubMed ID: 22353939). The authors did not provide any functional studies to help assess the pathogenicity of the c.1207C>T (p.Arg403Cys) variant. This variant is reported in 0.010% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Bardet-Biedl syndrome 2;C4225281:Retinitis pigmentosa 74

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 09, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.034

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Benign

0.52

DEOGEN2

Benign

0.27

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.39

T;.

M_CAP

Benign

0.042

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-0.73

PrimateAI

Benign

0.26

PROVEAN

Benign

0.75

N;N

REVEL

Uncertain

0.54

Sift

Benign

0.26

T;T

Sift4G

Benign

0.20

T;T

Vest4

0.69

MVP

0.60

MPC

0.34

ClinPred

0.027

GERP RS

-3.8

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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