2-169487811-G-A

Position:

• chr2-169487811-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The ENST00000295240.8(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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: BBS5 ENST00000295240.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.48

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-169487811-G-A is Pathogenic according to our data. Variant chr2-169487811-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169487811-G-A is described in Lovd as [Pathogenic]. Variant chr2-169487811-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BBS5	NM_152384.3	c.214G>A	p.Gly72Ser	missense_variant	4/12	ENST00000295240.8	NP_689597.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BBS5	ENST00000295240.8	c.214G>A	p.Gly72Ser	missense_variant	4/12	1	NM_152384.3	ENSP00000295240	P1
BBS5	ENST00000392663.6	c.214G>A	p.Gly72Ser	missense_variant	4/11	1		ENSP00000376431
BBS5	ENST00000475571.1	n.50G>A		non_coding_transcript_exon_variant	1/2	4
BBS5	ENST00000443151.1	c.143-176G>A		intron_variant, NMD_transcript_variant		5		ENSP00000406182

Frequencies

GnomAD3 genomes AF: 0.00000663 AC: 1 AN: 150920 Hom.: 0 Cov.: 32

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: 6 AN: 1455030 Hom.: 0 Cov.: 29 AF XY: 0.00000414 AC XY: 3 AN XY: 724236

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000663 AC: 1 AN: 150920 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73594

Gnomad4 AFR AF: 0.0000244

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bardet-Biedl syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 05, 2021	Variant summary: BBS5 c.214G>A (p.Gly72Ser) results in a non-conservative amino acid change located in the first DM16 repeat (IPR014003) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.7e-06 in 149692 control chromosomes (gnomAD v3.1, genomes dataset). The variant, c.214G>A, has been reported in the literature in multiple homozygous individuals of African origin, who were affected with Bardet-Biedl Syndrome (Hjortshoj_2008, Janssen_2011, Jespersgaard_2019, Habibi_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication also reported experimental evidence, and demonstrated that the variant affected ciliogenesis and impaired hedgehog signaling in fibroblasts that were derived from homozygous patients (Brunbjerg Hey_2021). One submitter has provided clinical-significance assessment for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 06, 2023	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 72 of the BBS5 protein (p.Gly72Ser). This variant is present in population databases (rs121908581, gnomAD 0.01%). This missense change has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 18203199). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6161). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BBS5 protein function with a positive predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -

Bardet-Biedl syndrome 5 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 15, 2008	- -
Likely pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;.;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	3.0	M;M;.
MutationTaster	Benign	1.0	A;A;A
PROVEAN	Pathogenic	-5.8	D;D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.63
MutPred		0.74		Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);
MVP		0.97
MPC		1.1
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.91
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
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

LitVar

Other links and lift over

dbSNP: rs121908581; hg19: chr2-170344321;