16-56499892-T-G

Variant names:

• chr16-56499892-T-G
• rs35294865
• NM_031885.5:c.1413A>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_031885.5(BBS2):​c.1413A>C​(p.Val471Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0156 in 1,614,088 control chromosomes in the GnomAD database, including 270 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V471V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.014 (31 hom., cov: 32)
  • Exomes 𝑓: 0.016 (239 hom.)
• Consequence: BBS2 NM_031885.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.47
• 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: Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Myriad Women’s Health
• BBS2-related 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

ENSG00000288725 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 16-56499892-T-G is Benign according to our data. Variant chr16-56499892-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.47 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0136 (2064/152316) while in subpopulation NFE AF = 0.018 (1224/68034). AF 95% confidence interval is 0.0172. There are 31 homozygotes in GnomAd4. There are 1092 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 31 AD,AR gene

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.1413A>C	p.Val471Val	synonymous	Exon 12 of 17	NP_114091.4
	BBS2	NM_001377456.1		c.1413A>C	p.Val471Val	synonymous	Exon 12 of 18	NP_001364385.1	Q9BXC9
	BBS2	NR_165293.1		n.1575A>C		non_coding_transcript_exon	Exon 12 of 17

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS2	ENST00000245157.11	TSL:1 MANE Select	c.1413A>C	p.Val471Val	synonymous	Exon 12 of 17	ENSP00000245157.5	Q9BXC9
	BBS2	ENST00000565781.6	TSL:1	n.3735A>C		non_coding_transcript_exon	Exon 8 of 12
	ENSG00000288725	ENST00000684388.1		n.333A>C		non_coding_transcript_exon	Exon 3 of 14	ENSP00000507647.1	A0A804HJU2

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 2064 AN: 152198 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.00316

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0451

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0180

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.0139 AC: 3487 AN: 251470 AF XY: 0.0136

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.0100

Gnomad ASJ exome AF: 0.00843

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0400

Gnomad NFE exome AF: 0.0174

Gnomad OTH exome AF: 0.0182

GnomAD4 exome AF: 0.0158 AC: 23091 AN: 1461772 Hom.: 239 Cov.: 30 AF XY: 0.0154 AC XY: 11184 AN XY: 727188

African (AFR) AF: 0.00233 AC: 78 AN: 33472

American (AMR) AF: 0.0102 AC: 457 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00850 AC: 222 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39684

South Asian (SAS) AF: 0.00196 AC: 169 AN: 86256

European-Finnish (FIN) AF: 0.0382 AC: 2043 AN: 53412

Middle Eastern (MID) AF: 0.0196 AC: 113 AN: 5768

European-Non Finnish (NFE) AF: 0.0173 AC: 19291 AN: 1111946

Other (OTH) AF: 0.0119 AC: 716 AN: 60384

GnomAD4 genome AF: 0.0136 AC: 2064 AN: 152316 Hom.: 31 Cov.: 32 AF XY: 0.0147 AC XY: 1092 AN XY: 74482

African (AFR) AF: 0.00315 AC: 131 AN: 41570

American (AMR) AF: 0.0109 AC: 166 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.0451 AC: 479 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0180 AC: 1224 AN: 68034

Other (OTH) AF: 0.0118 AC: 25 AN: 2112

Alfa AF: 0.0149 Hom.: 19

Bravo AF: 0.0107

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0182

EpiControl AF: 0.0213

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Bardet-Biedl syndrome 2 (3)
-	-	2	Bardet-Biedl syndrome 1 (2)
-	-	2	not specified (2)
-	-	1	Bardet-Biedl syndrome (1)
-	-	1	Bardet-Biedl syndrome 2;C4225281:Retinitis pigmentosa 74 (1)
-	-	1	not provided (1)
-	-	1	Retinitis pigmentosa 74 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	2.3
DANN	Benign	0.72
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35294865; hg19: chr16-56533804; COSMIC: COSV104392599;