chr4-122743090-G-C

Variant names:

• chr4-122743090-G-C
• rs771136797
• NM_152618.3:c.1198G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152618.3(BBS12):​c.1198G>C​(p.Val400Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V400M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BBS12 NM_152618.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.722
• Publications: 3 publications found

Genes affected

BBS12 (HGNC:26648): (Bardet-Biedl syndrome 12) The protein encoded by this gene is part of a complex that is involved in membrane trafficking. The encoded protein is a molecular chaperone that aids in protein folding upon ATP hydrolysis. This protein also plays a role in adipocyte differentiation. Defects in this gene are a cause of Bardet-Biedl syndrome type 12. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, May 2010]

BBS12 Gene-Disease associations (from GenCC):

• Bardet-Biedl syndrome 12

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Ambry Genetics, Myriad Women’s Health
• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16817966).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152618.3. 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
	BBS12	NM_152618.3	MANE Select	c.1198G>C	p.Val400Leu	missense	Exon 2 of 2	NP_689831.2
	BBS12	NM_001178007.2		c.1198G>C	p.Val400Leu	missense	Exon 3 of 3	NP_001171478.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS12	ENST00000314218.8	TSL:1 MANE Select	c.1198G>C	p.Val400Leu	missense	Exon 2 of 2	ENSP00000319062.3
	BBS12	ENST00000542236.5	TSL:2	c.1198G>C	p.Val400Leu	missense	Exon 3 of 3	ENSP00000438273.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 69

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	7.3
DANN	Benign	0.78
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.72
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.21
Sift	Benign	0.063	T
Sift4G	Benign	0.086	T
Polyphen		0.16	B
Vest4		0.24
MutPred		0.50		Gain of disorder (P = 0.2018)
MVP		0.92
MPC		0.14
ClinPred		0.19	T
GERP RS		1.9
Varity_R		0.066
gMVP		0.45
Mutation Taster		=56/44	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: rs771136797; hg19: chr4-123664245;