16-56519765-G-C

Position:

• chr16-56519765-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_031885.5(BBS2):​c.98C>G​(p.Ala33Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,234 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A33D) has been classified as Pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: BBS2 NM_031885.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.10

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-56519765-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BBS2	NM_031885.5	c.98C>G	p.Ala33Gly	missense_variant	1/17	ENST00000245157.11	NP_114091.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BBS2	ENST00000245157.11	c.98C>G	p.Ala33Gly	missense_variant	1/17	1	NM_031885.5	ENSP00000245157.5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152234 Hom.: 0 Cov.: 32

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

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74374

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

Alfa AF: 0.0000540 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D;.
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;.
M_CAP	Benign	0.046	D
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Benign	-0.79	T
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Benign	0.25
Sift	Benign	0.14	T;T
Sift4G	Benign	0.21	T;T
Vest4		0.63
MutPred		0.60		Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);
MVP		0.59
MPC		0.35
ClinPred		0.95	D
GERP RS		5.5
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs797045155; hg19: chr16-56553677;