rs764867200

Variant names:

• chr7-155298380-C-G
• rs764867200
• NM_005542.6:c.95C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005542.6(INSIG1):​c.95C>G​(p.Ala32Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,535,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: INSIG1 NM_005542.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.99
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.047781438).

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.95C>G	p.Ala32Gly	missense	Exon 2 of 6	NP_005533.2
	INSIG1	NM_001346590.2		c.95C>G	p.Ala32Gly	missense	Exon 2 of 7	NP_001333519.1	A4D2M9
	INSIG1	NM_001346591.2		c.95C>G	p.Ala32Gly	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.95C>G	p.Ala32Gly	missense	Exon 2 of 6	ENSP00000344741.4	O15503-1
	INSIG1	ENST00000885536.1		c.95C>G	p.Ala32Gly	missense	Exon 2 of 6	ENSP00000555595.1
	INSIG1	ENST00000885537.1		c.95C>G	p.Ala32Gly	missense	Exon 2 of 6	ENSP00000555596.1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000184 AC: 27 AN: 146632 AF XY: 0.000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000502

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000671

Gnomad NFE exome AF: 0.000356

Gnomad OTH exome AF: 0.000550

GnomAD4 exome AF: 0.000122 AC: 169 AN: 1383522 Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 83 AN XY: 683136

African (AFR) AF: 0.00 AC: 0 AN: 29780

American (AMR) AF: 0.0000328 AC: 1 AN: 30520

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22040

East Asian (EAS) AF: 0.00 AC: 0 AN: 36954

South Asian (SAS) AF: 0.00 AC: 0 AN: 75776

European-Finnish (FIN) AF: 0.0000415 AC: 2 AN: 48224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5486

European-Non Finnish (NFE) AF: 0.000147 AC: 158 AN: 1077808

Other (OTH) AF: 0.000141 AC: 8 AN: 56934

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152204 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74370

African (AFR) AF: 0.0000241 AC: 1 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000165 Hom.: 0

Bravo AF: 0.000132

ExAC AF: 0.000254 AC: 29

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	0.073
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		2.0
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.047
Sift	Benign	0.16	T
Sift4G	Benign	0.094	T
Polyphen		0.28	B
Vest4		0.084
MVP		0.45
MPC		0.97
ClinPred		0.038	T
GERP RS		2.4
PromoterAI		-0.093	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.097
gMVP		0.47
Mutation Taster		=92/8	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: rs764867200; hg19: chr7-155090090;