NM_005542.6:c.65C>G

Variant names:

• chr7-155298350-C-G
• rs773664641
• NM_005542.6:c.65C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005542.6(INSIG1):​c.65C>G​(p.Pro22Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000221 in 1,359,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: INSIG1 NM_005542.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.763
• 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]

INSIG1-DT (HGNC:55155): (INSIG1 divergent transcript)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.036013484).

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.65C>G	p.Pro22Arg	missense	Exon 2 of 6	NP_005533.2
	INSIG1	NM_001346590.2		c.65C>G	p.Pro22Arg	missense	Exon 2 of 7	NP_001333519.1	A4D2M9
	INSIG1	NM_001346591.2		c.65C>G	p.Pro22Arg	missense	Exon 2 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.65C>G	p.Pro22Arg	missense	Exon 2 of 6	ENSP00000344741.4	O15503-1
	INSIG1	ENST00000885536.1		c.65C>G	p.Pro22Arg	missense	Exon 2 of 6	ENSP00000555595.1
	INSIG1	ENST00000885537.1		c.65C>G	p.Pro22Arg	missense	Exon 2 of 6	ENSP00000555596.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000149 AC: 2 AN: 134434 AF XY: 0.0000136

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000115

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000221 AC: 3 AN: 1359880 Hom.: 0 Cov.: 31 AF XY: 0.00000149 AC XY: 1 AN XY: 669426

African (AFR) AF: 0.00 AC: 0 AN: 28100

American (AMR) AF: 0.000113 AC: 3 AN: 26554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19428

East Asian (EAS) AF: 0.00 AC: 0 AN: 36898

South Asian (SAS) AF: 0.00 AC: 0 AN: 69308

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1070890

Other (OTH) AF: 0.00 AC: 0 AN: 55820

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000872 AC: 1

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	Benign	0.051
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	7.6
DANN	Benign	0.88
DEOGEN2	Benign	0.085	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N
PhyloP100		0.76
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.018
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.0	B
Vest4		0.24
MutPred		0.29		Loss of glycosylation at P22 (P = 0.0057)
MVP		0.17
MPC		0.89
ClinPred		0.055	T
GERP RS		-3.9
PromoterAI		0.012	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.027
gMVP		0.23
Mutation Taster		=95/5	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: rs773664641; hg19: chr7-155090060;