16-56514681-C-G

Variant names:

• chr16-56514681-C-G
• rs587777825
• NM_031885.5:c.118-1G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_031885.5(BBS2):​c.118-1G>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BBS2 NM_031885.5 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.67
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Bardet-Biedl syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Myriad Women’s Health
• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa 74

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.10526316 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7, offset of -28, new splice context is: ctaattttttatattttaAGgga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-56514681-C-G is Pathogenic according to our data. Variant chr16-56514681-C-G is described in CliVar as Pathogenic. Clinvar id is 4579.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-56514681-C-G is described in CliVar as Pathogenic. Clinvar id is 4579.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-56514681-C-G is described in CliVar as Pathogenic. Clinvar id is 4579.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-56514681-C-G is described in CliVar as Pathogenic. Clinvar id is 4579.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-56514681-C-G is described in CliVar as Pathogenic. Clinvar id is 4579.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-56514681-C-G is described in CliVar as Pathogenic. Clinvar id is 4579.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-56514681-C-G is described in CliVar as Pathogenic. Clinvar id is 4579.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-56514681-C-G is described in CliVar as Pathogenic. Clinvar id is 4579.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-56514681-C-G is described in CliVar as Pathogenic. Clinvar id is 4579.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-56514681-C-G is described in CliVar as Pathogenic. Clinvar id is 4579.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-56514681-C-G is described in CliVar as Pathogenic. Clinvar id is 4579.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-56514681-C-G is described in CliVar as Pathogenic. Clinvar id is 4579.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-56514681-C-G is described in CliVar as Pathogenic. Clinvar id is 4579.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-56514681-C-G is described in CliVar as Pathogenic. Clinvar id is 4579.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-56514681-C-G is described in CliVar as Pathogenic. Clinvar id is 4579.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-56514681-C-G is described in CliVar as Pathogenic. Clinvar id is 4579.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-56514681-C-G is described in CliVar as Pathogenic. Clinvar id is 4579.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-56514681-C-G is described in CliVar as Pathogenic. Clinvar id is 4579.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-56514681-C-G is described in CliVar as Pathogenic. Clinvar id is 4579.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-56514681-C-G is described in CliVar as Pathogenic. Clinvar id is 4579.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-56514681-C-G is described in CliVar as Pathogenic. Clinvar id is 4579.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-56514681-C-G is described in CliVar as Pathogenic. Clinvar id is 4579.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-56514681-C-G is described in CliVar as Pathogenic. Clinvar id is 4579.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-56514681-C-G is described in CliVar as Pathogenic. Clinvar id is 4579.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BBS2	NM_031885.5	c.118-1G>C		splice_acceptor_variant, intron_variant	Intron 1 of 16	ENST00000245157.11	NP_114091.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BBS2	ENST00000245157.11	c.118-1G>C		splice_acceptor_variant, intron_variant	Intron 1 of 16	1	NM_031885.5	ENSP00000245157.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Bardet-Biedl syndrome 2 Pathogenic:1

Sep 21, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.7
GERP RS		5.5
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.49		Position offset: -34
DS_AL_spliceai		0.99		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587777825; hg19: chr16-56548593;