7-155301638-C-G

Variant names:

• chr7-155301638-C-G
• NM_005542.6:c.485C>G

Variant summary

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

The NM_005542.6(INSIG1):​c.485C>G​(p.Ala162Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: INSIG1 NM_005542.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.62
• Publications: 0 publications found

Genes affected

INSIG1 (HGNC:6083): (insulin induced gene 1) This gene encodes an endoplasmic reticulum membrane protein that regulates cholesterol metabolism, lipogenesis, and glucose homeostasis. The encoded protein has six transmembrane helices which contain an effector protein binding site. It binds the sterol-sensing domains of sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), and is essential for the sterol-mediated trafficking of these two proteins. It promotes the endoplasmic reticulum retention of SCAP and the ubiquitin-mediated degradation of HMG-CoA reductase. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005542.6. 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
	INSIG1	NM_005542.6	MANE Select	c.485C>G	p.Ala162Gly	missense	Exon 3 of 6	NP_005533.2
	INSIG1	NM_001346590.2		c.485C>G	p.Ala162Gly	missense	Exon 3 of 7	NP_001333519.1	A4D2M9
	INSIG1	NM_001346591.2		c.485C>G	p.Ala162Gly	missense	Exon 3 of 7	NP_001333520.1	A4D2M9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSIG1	ENST00000340368.9	TSL:1 MANE Select	c.485C>G	p.Ala162Gly	missense	Exon 3 of 6	ENSP00000344741.4	O15503-1
	INSIG1	ENST00000885536.1		c.485C>G	p.Ala162Gly	missense	Exon 3 of 6	ENSP00000555595.1
	INSIG1	ENST00000885537.1		c.485C>G	p.Ala162Gly	missense	Exon 3 of 6	ENSP00000555596.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0097	T
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.6	L
PhyloP100		7.6
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.14
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.024	D
Polyphen		0.99	D
Vest4		0.53
MutPred		0.54		Gain of sheet (P = 0.0266)
MVP		0.66
MPC		1.9
ClinPred		0.89	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.36
gMVP		0.70
Mutation Taster		=32/68	disease causing

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

hg19: chr7-155093348;