16-56497063-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_031885.5(BBS2):c.1814C>G(p.Ser605*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,612,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

BBS2
NM_031885.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.92

Publications

2 publications found

Variant links:

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

BBS2 links:

ENSG00000288725 (HGNC:):

ENSG00000288725 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-56497063-G-C is Pathogenic according to our data. Variant chr16-56497063-G-C is described in CliVar as Pathogenic. Clinvar id is 553335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56497063-G-C is described in CliVar as Pathogenic. Clinvar id is 553335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56497063-G-C is described in CliVar as Pathogenic. Clinvar id is 553335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56497063-G-C is described in CliVar as Pathogenic. Clinvar id is 553335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56497063-G-C is described in CliVar as Pathogenic. Clinvar id is 553335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56497063-G-C is described in CliVar as Pathogenic. Clinvar id is 553335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56497063-G-C is described in CliVar as Pathogenic. Clinvar id is 553335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56497063-G-C is described in CliVar as Pathogenic. Clinvar id is 553335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56497063-G-C is described in CliVar as Pathogenic. Clinvar id is 553335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56497063-G-C is described in CliVar as Pathogenic. Clinvar id is 553335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56497063-G-C is described in CliVar as Pathogenic. Clinvar id is 553335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56497063-G-C is described in CliVar as Pathogenic. Clinvar id is 553335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56497063-G-C is described in CliVar as Pathogenic. Clinvar id is 553335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56497063-G-C is described in CliVar as Pathogenic. Clinvar id is 553335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56497063-G-C is described in CliVar as Pathogenic. Clinvar id is 553335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56497063-G-C is described in CliVar as Pathogenic. Clinvar id is 553335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56497063-G-C is described in CliVar as Pathogenic. Clinvar id is 553335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56497063-G-C is described in CliVar as Pathogenic. Clinvar id is 553335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56497063-G-C is described in CliVar as Pathogenic. Clinvar id is 553335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56497063-G-C is described in CliVar as Pathogenic. Clinvar id is 553335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56497063-G-C is described in CliVar as Pathogenic. Clinvar id is 553335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56497063-G-C is described in CliVar as Pathogenic. Clinvar id is 553335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56497063-G-C is described in CliVar as Pathogenic. Clinvar id is 553335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BBS2	NM_031885.5 link	c.1814C>G	p.Ser605*	stop_gained	Exon 15 of 17	ENST00000245157.11	NP_114091.4	Q9BXC9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BBS2	ENST00000245157.11 link	c.1814C>G	p.Ser605*	stop_gained	Exon 15 of 17	1	NM_031885.5	ENSP00000245157.5		Q9BXC9
ENSG00000288725	ENST00000684388.1 link	n.734C>G		non_coding_transcript_exon_variant	Exon 6 of 14			ENSP00000507647.1		A0A804HJU2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000795

AC:

AN:

251422

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460248

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726550

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33446

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110530

Other (OTH)

AF:

0.0000166

AC:

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0000240

AC:

AN:

41580

American (AMR)

AF:

0.00

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bardet-Biedl syndrome 2

Pathogenic:3

Department of Pediatrics, National Cheng-Kung University Hospital

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 15, 2017

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

May 13, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bardet-Biedl syndrome

Pathogenic:1

Aug 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 553335). This premature translational stop signal has been observed in individual(s) with BBS2-related conditions (PMID: 25999675, 27659767). This variant is present in population databases (rs201063733, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Ser605*) in the BBS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BBS2 are known to be pathogenic (PMID: 11285252, 20177705, 24608809, 26518167). -

Bardet-Biedl syndrome 2;C4225281:Retinitis pigmentosa 74

Pathogenic:1

Dec 15, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.66

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

1.0

PhyloP100

7.9

Vest4

0.82, 0.83

GERP RS

5.1

Mutation Taster

=8/192

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over