2-169487811-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3PM2PP2PP5_Very_Strong

The NM_152384.3(BBS5):c.214G>A(p.Gly72Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000436 in 1,605,950 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002015184: The variant affected ciliogenesis and impaired hedgehog signaling in fibroblasts that were derived from homozygous patients (Brunbjerg Hey_2021).".

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

BBS5
NM_152384.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 5.48

Publications

8 publications found

Variant links:

Genes affected

BBS5 (HGNC:970): (Bardet-Biedl syndrome 5) This gene encodes a protein that has been directly linked to Bardet-Biedl syndrome. The primary features of this syndrome include retinal dystrophy, obesity, polydactyly, renal abnormalities and learning disabilities. Experimentation in non-human eukaryotes suggests that this gene is expressed in ciliated cells and that it is required for the formation of cilia. Alternate transcriptional splice variants have been observed but have not been fully characterized. [provided by RefSeq, Jul 2008]

BBS5 Gene-Disease associations (from GenCC):

Bardet-Biedl syndrome 5
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P
BBS5-related ciliopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Bardet-Biedl syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

BBS5 links:

ENSG00000251569 (HGNC:):

ENSG00000251569 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV002015184: The variant affected ciliogenesis and impaired hedgehog signaling in fibroblasts that were derived from homozygous patients (Brunbjerg Hey_2021).

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.85025 (below the threshold of 3.09). Trascript score misZ: 1.0056 (below the threshold of 3.09). GenCC associations: The gene is linked to Bardet-Biedl syndrome 5, BBS5-related ciliopathy, Bardet-Biedl syndrome.

PP5

Variant 2-169487811-G-A is Pathogenic according to our data. Variant chr2-169487811-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 6161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152384.3. 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
	BBS5	NM_152384.3	MANE Select	c.214G>A	p.Gly72Ser	missense	Exon 4 of 12	NP_689597.1	A0A0S2Z626

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BBS5	ENST00000295240.8	TSL:1 MANE Select	c.214G>A	p.Gly72Ser	missense	Exon 4 of 12	ENSP00000295240.3	Q8N3I7-1
ENSG00000251569	ENST00000513963.1	TSL:2	c.214G>A	p.Gly72Ser	missense	Exon 4 of 16	ENSP00000424363.1	E9PBE3
BBS5	ENST00000392663.6	TSL:1	c.214G>A	p.Gly72Ser	missense	Exon 4 of 11	ENSP00000376431.2	Q8N3I7-2

Frequencies

GnomAD3 genomes

AF:

0.00000663

AC:

AN:

150920

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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

GnomAD4 exome

AF:

0.00000412

AC:

AN:

1455030

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

724236

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33280

American (AMR)

AF:

0.00

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26058

East Asian (EAS)

AF:

0.00

AC:

AN:

39516

South Asian (SAS)

AF:

0.0000233

AC:

AN:

85942

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5252

European-Non Finnish (NFE)

AF:

0.00000271

AC:

AN:

1106788

Other (OTH)

AF:

0.00

AC:

AN:

60140

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.433

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:

0.00000663

AC:

AN:

150920

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73594

show subpopulations

African (AFR)

AF:

0.0000244

AC:

AN:

41024

American (AMR)

AF:

0.00

AC:

AN:

15146

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4788

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10214

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67828

Other (OTH)

AF:

0.00

AC:

AN:

2058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Bardet-Biedl syndrome (4)

Bardet-Biedl syndrome 5 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.74

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.60

MetaSVM

Uncertain

0.70

MutationAssessor

Pathogenic

3.0

PhyloP100

5.5

PROVEAN

Pathogenic

-5.8

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.63

MutPred

0.74

Loss of helix (P = 0.0068)

MVP

0.97

MPC

1.1

ClinPred

1.0

GERP RS

5.7

Varity_R

0.91

gMVP

0.85

Mutation Taster

=10/90

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.30

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.30

Position offset: -5

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over