rs121908179

chr16-56514487-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_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 (★★). Synonymous variant affecting the same amino acid position (i.e. D104D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: BBS2 NM_031885.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 7.86

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 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/exons	MANE	UniProt
BBS2	NM_031885.5	c.311A>C	p.Asp104Ala	missense_variant	2/17	ENST00000245157.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS2	ENST00000245157.11	c.311A>C	p.Asp104Ala	missense_variant	2/17	1	NM_031885.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152178 Hom.: 0 Cov.: 32

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: 11 AN: 251464 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135910

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: 42 AN: 1461854 Hom.: 0 Cov.: 30 AF XY: 0.0000371 AC XY: 27 AN XY: 727230

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: 4 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74338

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.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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.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). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2015	- -

Bardet-Biedl syndrome 2 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 31, 2023	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jan 30, 2017	- -

Bardet-Biedl syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	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). 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	Jun 30, 2016	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. -

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

Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Feb 23, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 12, 2022	- -

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.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. -
Pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -

Bardet-biedl syndrome 1/2, digenic Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2015

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 15, 2019

Published functional studies demonstrate a damaging effect suggestive of a dominant negative mode of action (Zaghloul et al., 2010); This variant is associated with the following publications: (PMID: 31456290, 20498079, 23829372, 11567139, 19402160, 25541840) -

BBS2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 26, 2023

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 (OMIM #615981), retinitis pigmentosa 74 (OMIM #616562), 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	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D;.
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.47	D
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.7	D;D
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	D
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

Other links and lift over

dbSNP: rs121908179; hg19: chr16-56548399;