2-169487103-G-C

Variant names:

• chr2-169487103-G-C
• rs767221160
• NM_152384.3:c.177G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_152384.3(BBS5):​c.177G>C​(p.Trp59Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BBS5 NM_152384.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.55
• Publications: 0 publications found

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: G2P, Genomics England PanelApp, Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000251569 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_152384.3
• 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, Bardet-Biedl syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS5	NM_152384.3	MANE Select	c.177G>C	p.Trp59Cys	missense	Exon 3 of 12	NP_689597.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS5	ENST00000295240.8	TSL:1 MANE Select	c.177G>C	p.Trp59Cys	missense	Exon 3 of 12	ENSP00000295240.3
	ENSG00000251569	ENST00000513963.1	TSL:2	c.177G>C	p.Trp59Cys	missense	Exon 3 of 16	ENSP00000424363.1
	BBS5	ENST00000392663.6	TSL:1	c.177G>C	p.Trp59Cys	missense	Exon 3 of 11	ENSP00000376431.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.6
PROVEAN	Pathogenic	-13	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.81		Loss of sheet (P = 3e-04)
MVP		1.0
MPC		1.4
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.95
gMVP		0.92
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs767221160; hg19: chr2-170343613;