16-56519765-G-T

Position:

chr16-56519765-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_031885.5(BBS2):c.98C>A(p.Ala33Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,096 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A33A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

BBS2
NM_031885.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2

Conservation

PhyloP100: 9.10

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 Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_031885.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.851

PP5

Variant 16-56519765-G-T is Pathogenic according to our data. Variant chr16-56519765-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 209042.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=2, Likely_pathogenic=1}. Variant chr16-56519765-G-T is described in Lovd as [Pathogenic]. Variant chr16-56519765-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS2	NM_031885.5 linkuse as main transcript	c.98C>A	p.Ala33Asp	missense_variant	1/17	ENST00000245157.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS2	ENST00000245157.11 linkuse as main transcript	c.98C>A	p.Ala33Asp	missense_variant	1/17	1	NM_031885.5	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152234

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:

0.00

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:

0.00000805

AC:

AN:

248348

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134842

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000892

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460862

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726724

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

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

Bravo

AF:

0.0000113

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Bardet-Biedl syndrome 2

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 01, 2021	PM2, PP3, PP4, PP5 -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 15, 2021	NM_031885.3(BBS2):c.98C>A(A33D) is a missense variant classified as a variant of uncertain significance in the context of Bardet-Biedl syndrome, BBS2-related. A33D has not been observed in cases with relevant disease. Functional assessments of this variant are not available in the literature. A33D has been observed in population frequency databases (gnomAD: AMR 0.003%). In summary, there is insufficient evidence to classify NM_031885.3(BBS2):c.98C>A(A33D) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

Retinitis pigmentosa 74

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2015

- -

Bardet-Biedl syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 29, 2023

This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 33 of the BBS2 protein (p.Ala33Asp). This variant is present in population databases (rs797045155, gnomAD 0.003%). This missense change has been observed in individual(s) with Bardet-Biedl syndrome and/or nonsyndromic retinitis pigmentosa (PMID: 25541840; Invitae). 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: 209042). 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. For these reasons, this variant has been classified as Pathogenic. -

Retinitis pigmentosa

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Sharon lab, Hadassah-Hebrew University Medical Center

Jun 23, 2019

- -

BBS2-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 01, 2024

The BBS2 c.98C>A variant is predicted to result in the amino acid substitution p.Ala33Asp. This variant was reported in the compound heterozygous state in three siblings who presented with retinitis pigmentosa (Shevach et al. 2015. PubMed ID: 25541840). This variant was also described in the apparently homozygous state in at least two other individuals with retinitis pigmentosa or suspected Bardet-Biedl syndrome; however, additional clinical and familial details were not provided (Sharon et al. 2019. PubMed ID: 31456290, supplementary data; Marinakis et al. 2021. PubMed ID: 34008892). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

D;.

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

D;.

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.85

D;D

MetaSVM

Uncertain

-0.0021

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.5

D;D

REVEL

Pathogenic

0.87

Sift

Uncertain

0.015

D;D

Sift4G

Uncertain

0.028

D;D

Vest4

0.95

MutPred

0.61

Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);

MVP

0.82

MPC

1.1

ClinPred

0.98

GERP RS

5.5

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