chr2-118096585-G-A

Position:

• chr2-118096585-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016133.4(INSIG2):​c.29G>A​(p.Gly10Glu) 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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: INSIG2 NM_016133.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.73

Genes affected

INSIG2 (HGNC:20452): (insulin induced gene 2) The protein encoded by this gene is highly similar to the protein product encoded by gene INSIG1. Both INSIG1 protein and this protein are endoplasmic reticulum proteins that block the processing of sterol regulatory element binding proteins (SREBPs) by binding to SREBP cleavage-activating protein (SCAP), and thus prevent SCAP from escorting SREBPs to the Golgi. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09929854).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INSIG2	NM_016133.4	c.29G>A	p.Gly10Glu	missense_variant	2/6	ENST00000245787.9	NP_057217.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INSIG2	ENST00000245787.9	c.29G>A	p.Gly10Glu	missense_variant	2/6	1	NM_016133.4	ENSP00000245787	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 15, 2024

The c.29G>A (p.G10E) alteration is located in exon 2 (coding exon 1) of the INSIG2 gene. This alteration results from a G to A substitution at nucleotide position 29, causing the glycine (G) at amino acid position 10 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	17
DANN	Benign	0.53
DEOGEN2	Benign	0.097	T;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.091
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.099	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;.
MutationTaster	Benign	0.94	N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.26	N;.
REVEL	Benign	0.070
Sift	Benign	0.92	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;.
Vest4		0.20
MutPred		0.28		Gain of solvent accessibility (P = 0.1045);Gain of solvent accessibility (P = 0.1045);
MVP		0.62
MPC		0.90
ClinPred		0.11	T
GERP RS		4.5
Varity_R		0.090
gMVP		0.41

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-118854161;