16-56509915-A-G

Variant names:

• chr16-56509915-A-G
• rs191207351
• NM_031885.5:c.612+42T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_031885.5(BBS2):​c.612+42T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00954 in 1,595,852 control chromosomes in the GnomAD database, including 99 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0098 (91 hom.)
• Consequence: BBS2 NM_031885.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00300
• Publications: 0 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 16-56509915-A-G is Benign according to our data. Variant chr16-56509915-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 261982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00693 (1054/152178) while in subpopulation NFE AF = 0.0116 (789/67998). AF 95% confidence interval is 0.0109. There are 8 homozygotes in GnomAd4. There are 495 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS2	NM_031885.5	MANE Select	c.612+42T>C		intron	N/A	NP_114091.4
	BBS2	NM_001377456.1		c.612+42T>C		intron	N/A	NP_001364385.1
	BBS2	NR_165293.1		n.774+42T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS2	ENST00000245157.11	TSL:1 MANE Select	c.612+42T>C		intron	N/A	ENSP00000245157.5
	BBS2	ENST00000565781.6	TSL:1	n.626+42T>C		intron	N/A
	BBS2	ENST00000565859.2	TSL:3	n.309T>C		non_coding_transcript_exon	Exon 3 of 14

Frequencies

GnomAD3 genomes AF: 0.00693 AC: 1054 AN: 152060 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.00698 AC: 1755 AN: 251296 AF XY: 0.00713

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.00393

Gnomad ASJ exome AF: 0.00586

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00803

Gnomad NFE exome AF: 0.0112

Gnomad OTH exome AF: 0.00620

GnomAD4 exome AF: 0.00981 AC: 14168 AN: 1443674 Hom.: 91 Cov.: 26 AF XY: 0.00973 AC XY: 7001 AN XY: 719398

African (AFR) AF: 0.00172 AC: 57 AN: 33078

American (AMR) AF: 0.00403 AC: 180 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00542 AC: 141 AN: 26002

East Asian (EAS) AF: 0.00 AC: 0 AN: 39560

South Asian (SAS) AF: 0.00111 AC: 95 AN: 85810

European-Finnish (FIN) AF: 0.00708 AC: 377 AN: 53248

Middle Eastern (MID) AF: 0.00262 AC: 15 AN: 5720

European-Non Finnish (NFE) AF: 0.0117 AC: 12863 AN: 1095840

Other (OTH) AF: 0.00737 AC: 440 AN: 59736

GnomAD4 genome AF: 0.00693 AC: 1054 AN: 152178 Hom.: 8 Cov.: 32 AF XY: 0.00665 AC XY: 495 AN XY: 74384

African (AFR) AF: 0.00185 AC: 77 AN: 41524

American (AMR) AF: 0.00327 AC: 50 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.00944 AC: 100 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0116 AC: 789 AN: 67998

Other (OTH) AF: 0.00616 AC: 13 AN: 2110

Alfa AF: 0.0103 Hom.: 1

Bravo AF: 0.00674

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.16
DANN	Benign	0.57
PhyloP100		0.0030
Mutation Taster		=100/0	polymorphism

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: rs191207351; hg19: chr16-56543827; COSMIC: COSV104392617;