16-56496982-C-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PM5 PP5_Very_Strong

The NM_031885.5(BBS2):c.1895G>C(p.Arg632Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000663 in 1,613,452 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R632C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000063 (0 hom.)
• Consequence: BBS2 NM_031885.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:17
• Conservation: PhyloP100: 7.70

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-56496982-C-T is described in Lovd as [Pathogenic].
• PP5: Variant 16-56496982-C-G is Pathogenic according to our data. Variant chr16-56496982-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 4578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56496982-C-G is described in Lovd as [Pathogenic]. Variant chr16-56496982-C-G is described in Lovd as [Likely_pathogenic]. Variant chr16-56496982-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS2	NM_031885.5	c.1895G>C	p.Arg632Pro	missense_variant	15/17	ENST00000245157.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS2	ENST00000245157.11	c.1895G>C	p.Arg632Pro	missense_variant	15/17	1	NM_031885.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00404

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: 0.000115 AC: 29 AN: 251468 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000630 AC: 92 AN: 1461264 Hom.: 0 Cov.: 31 AF XY: 0.0000660 AC XY: 48 AN XY: 726952

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00249

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74338

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00404

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: 0.000245 Hom.: 0

Bravo AF: 0.0000869

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bardet-Biedl syndrome 2 Pathogenic:3

Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Mar 08, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 04, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2015	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 13, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 06, 2023	The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant appears to segregate with Bardet-Biedl syndrome in at least one family. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 20798079) In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. -

Retinitis pigmentosa 74 Pathogenic:2

Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 04, 2022	The heterozygous p.Arg632Pro 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 6 individuals of unknown and Ashkenazi Jewish ethnicities with retinitis pigmentosa 74 (PMID: 25133751, 25412400, 25541840, 28559085), and has been identified in 0.3% (29/10370) of Ashkenazi Jewish, 0.004% (1/25116) of European Finnish, and 0.0008% (1/129168) of European non-Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs138043021). 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: 4578) as pathogenic by Illumina Clinical Services Laboratory, Blueprint Genetics, Integrated Genetics/Laboratory Corporation of America, OMIM, and Sharon lab,Hadassah-Hebrew University Medical Center, and as likely pathogenic by Counsyl and Invitae. 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 4 affected homozygotes, in combination with a reported pathogenic variant, and in 6 individuals with retinitis pigmentosa 74 increases the likelihood that the p.Arg632Pro variant is pathogenic (Variation ID: 4570; PMID: 25133751, 25412400, 25541840, 28559085). 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 affected individuals. ACMG/AMP Criteria applied: PS3, PM3_strong, PP3 (Richards 2015). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2015	- -

Bardet-Biedl syndrome 2;C4225281:Retinitis pigmentosa 74 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 02, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Jul 22, 2022	- -

Bardet-Biedl syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 632 of the BBS2 protein (p.Arg632Pro). This variant is present in population databases (rs138043021, gnomAD 0.3%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 21052717, 22401627, 25133751, 25412400, 25541840, 28559085). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4578). 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 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 05, 2016	Variant summary: The c.1895G>C in BBS2 gene is a missense change that alters a conserved nucleotide and 4/4 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 0.012% exclusively in individuals of European descent (0.02%). This frequency does not exceed the maximal expected allele frequency for a pathogenic variant in BBS2 gene (0.085%). Fedick (2014) reports the carrier frequency of 0.261% (0.0064%) for Jewish population. The variant of interest has been reported in multiple BBS pts in compound heterozygous state (Katsanis, 2001, Bin, 2009, Daniels, 2012, Deveault, 2011, Fedick, 2014, and Shevach, 2014), one patient (compound heterozyote) with IRDs (Consugar, 2015), and in 4 individuals (2 homozygotes and 2 compound heterozygotes) presented with nonsyndromic autosomal recessive RP (Shevach, 2014). In functional studies the variant acted as null allele (Zaghloul, 2010). Taking together, the variant was classified as Pathogenic. -

Retinitis pigmentosa Pathogenic:2

Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Apr 01, 2021	The p.Arg632Pro 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. -
Pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 14, 2021

The c.1895G>C (p.R632P) alteration is located in exon 15 (coding exon 15) of the BBS2 gene. This alteration results from a G to C substitution at nucleotide position 1895, causing the arginine (R) at amino acid position 632 to be replaced by a proline (P). Based on data from the Genome Aggregation Database (gnomAD) database, the BBS2 c.1895G>C alteration was observed in 0.01% (32/282854) of total alleles studied, with a frequency of 0.28% (29/10370) in the Ashkenazi Jewish subpopulation. This alteration has been noted in a homozygous state in individuals presenting with retinitis pigmentosa (Watson, 2014; Shevach, 2015) and in a compound heterozygous state in individuals presenting with Bardet-Biedl syndrome (Janssen, 2011;Stone, 2017). This amino acid position is highly conserved in available vertebrate species. This alteration is located in the alpha-helical domain of BBS2. Functional evidence suggests that this alteration disrupts the formation of the alpha-helix, leading to impaired interaction between BBS2 and BBS9 (Zaghloul, 2010; Ludlam, 2019). The p.R632P alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

BBS2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

The BBS2 c.1895G>C (p.Arg632Pro) missense variant has been reported in six studies in which it is found in a total of 10 patients with BBS2-related disorders. The p.Arg632Pro variant was identified in a compound heterozygous state in four individuals with Bardet-Biedl syndrome (BBS), three of whom carry a third variant in another BBS-associated gene (Katsanis et al. 2001; Bin et al. 2009; Chen et al. 2011; Deveault et al. 2011). The p.Arg632Pro variant was also identified in patients with retinitis pigmentosa, in a homozygous state in four individuals and in a compound heterozygous state in two individuals (Watson et al. 2014; Shevach et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00021 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies using translation blocking morpholinos for bbs2 in zebrafish demonstrate that the variant was unable to rescue the phenotype and is therefore considered a null allele (Zaghloul et al. 2010). Based on the collective evidence, the p.Arg632Pro variant is classified as pathogenic for BBS2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jun 19, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;D;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;.
M_CAP	Pathogenic	0.51	D
MetaRNN	Uncertain	0.63	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.68	T
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.98, 0.96
MVP		0.97
MPC		1.1
ClinPred		0.96	D
GERP RS		5.1
gMVP		0.93

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

Other links and lift over

dbSNP: rs138043021; hg19: chr16-56530894;