chr16-56498434-T-C

Variant names:

• chr16-56498434-T-C
• rs6499838
• NM_031885.5:c.1659+3A>G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BA1

The NM_031885.5(BBS2):​c.1659+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0066 in 1,613,902 control chromosomes in the GnomAD database, including 622 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (325 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (297 hom.)
• Consequence: BBS2 NM_031885.5 splice_region, intron
• Scores: Splicing: ADA: 0.9914
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.65
• Publications: 5 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, Myriad Women’s Health
• BBS2-related ciliopathy

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

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

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000288725 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 16-56498434-T-C is Benign according to our data. Variant chr16-56498434-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031885.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS2	NM_031885.5	MANE Select	c.1659+3A>G		splice_region intron	N/A	NP_114091.4
	BBS2	NM_001377456.1		c.1659+3A>G		splice_region intron	N/A	NP_001364385.1	Q9BXC9
	BBS2	NR_165293.1		n.1949+3A>G		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS2	ENST00000245157.11	TSL:1 MANE Select	c.1659+3A>G		splice_region intron	N/A	ENSP00000245157.5	Q9BXC9
	BBS2	ENST00000565781.6	TSL:1	n.5190+3A>G		splice_region intron	N/A
	ENSG00000288725	ENST00000684388.1		n.579+3A>G		splice_region intron	N/A	ENSP00000507647.1	A0A804HJU2

Frequencies

GnomAD3 genomes AF: 0.0347 AC: 5274 AN: 152112 Hom.: 322 Cov.: 32

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0146

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.0272

GnomAD2 exomes AF: 0.00921 AC: 2314 AN: 251148 AF XY: 0.00655

Gnomad AFR exome AF: 0.122

Gnomad AMR exome AF: 0.00695

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000387

Gnomad OTH exome AF: 0.00506

GnomAD4 exome AF: 0.00367 AC: 5360 AN: 1461672 Hom.: 297 Cov.: 32 AF XY: 0.00316 AC XY: 2297 AN XY: 727144

African (AFR) AF: 0.121 AC: 4055 AN: 33466

American (AMR) AF: 0.00778 AC: 348 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00203 AC: 53 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39682

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86252

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53334

Middle Eastern (MID) AF: 0.00590 AC: 34 AN: 5766

European-Non Finnish (NFE) AF: 0.000301 AC: 335 AN: 1111936

Other (OTH) AF: 0.00850 AC: 513 AN: 60386

GnomAD4 genome AF: 0.0348 AC: 5294 AN: 152230 Hom.: 325 Cov.: 32 AF XY: 0.0339 AC XY: 2523 AN XY: 74420

African (AFR) AF: 0.120 AC: 4963 AN: 41514

American (AMR) AF: 0.0145 AC: 222 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000529 AC: 36 AN: 68022

Other (OTH) AF: 0.0270 AC: 57 AN: 2114

Alfa AF: 0.0156 Hom.: 239

Bravo AF: 0.0393

Asia WGS AF: 0.00693 AC: 25 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Bardet-Biedl syndrome 1 (2)
-	-	2	Bardet-Biedl syndrome 2 (2)
-	-	2	not specified (2)
-	-	1	Bardet-Biedl syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	15
DANN	Benign	0.77
PhyloP100		1.6
Mutation Taster		=91/9	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.84
SpliceAI score (max)		0.69		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.69		Position offset: 3

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

Other links and lift over

dbSNP: rs6499838; hg19: chr16-56532346; COSMIC: COSV104392578;