Genetic Variant INSIG1:p.Cys13Arg (chr7-155298322-T-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_005542.6(INSIG1):c.37T>C(p.Cys13Arg) 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. 14/22 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. C13S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

INSIG1
NM_005542.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.48

Publications

0 publications found

Variant links:

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 links:

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

INSIG1-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3548443).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
INSIG1	NM_005542.6	MANE Select	c.37T>C	p.Cys13Arg	missense	Exon 2 of 6	NP_005533.2
INSIG1	NM_001346590.2		c.37T>C	p.Cys13Arg	missense	Exon 2 of 7	NP_001333519.1	A4D2M9
INSIG1	NM_001346591.2		c.37T>C	p.Cys13Arg	missense	Exon 2 of 7	NP_001333520.1	A4D2M9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
INSIG1	ENST00000340368.9	TSL:1 MANE Select	c.37T>C	p.Cys13Arg	missense	Exon 2 of 6	ENSP00000344741.4	O15503-1
INSIG1	ENST00000885536.1		c.37T>C	p.Cys13Arg	missense	Exon 2 of 6	ENSP00000555595.1
INSIG1	ENST00000885537.1		c.37T>C	p.Cys13Arg	missense	Exon 2 of 6	ENSP00000555596.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1359156

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

669040

African (AFR)

AF:

0.00

AC:

AN:

27712

American (AMR)

AF:

0.00

AC:

AN:

26754

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19242

East Asian (EAS)

AF:

0.00

AC:

AN:

36880

South Asian (SAS)

AF:

0.00

AC:

AN:

68898

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47998

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5282

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1070630

Other (OTH)

AF:

0.00

AC:

AN:

55760

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.17

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.57

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.42

M_CAP

Benign

0.026

MetaRNN

Benign

0.35

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.1

PhyloP100

1.5

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.61

REVEL

Benign

0.14

Sift

Benign

0.22

Sift4G

Uncertain

0.041

Polyphen

0.73

Vest4

0.50

MutPred

0.54

Gain of MoRF binding (P = 0.0103)

MVP

0.46

MPC

2.0

ClinPred

0.77

GERP RS

1.6

PromoterAI

0.027

Neutral

(source)

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.9

Varity_R

0.18

gMVP

0.70

Mutation Taster

=54/46

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over