NM_000208.4:c.84C>G

Variant names:

• chr19-7293808-G-C
• NM_000208.4:c.84C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000208.4(INSR):​c.84C>G​(p.His28Gln) 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. 14/21 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: INSR NM_000208.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.447

Genes affected

INSR (HGNC:6091): (insulin receptor) This gene encodes a member of the receptor tyrosine kinase family of proteins. The encoded preproprotein is proteolytically processed to generate alpha and beta subunits that form a heterotetrameric receptor. Binding of insulin or other ligands to this receptor activates the insulin signaling pathway, which regulates glucose uptake and release, as well as the synthesis and storage of carbohydrates, lipids and protein. Mutations in this gene underlie the inherited severe insulin resistance syndromes including type A insulin resistance syndrome, Donohue syndrome and Rabson-Mendenhall syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the INSR gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 3.8314 (above the threshold of 3.09). Trascript score misZ: 5.4593 (above the threshold of 3.09). GenCC associations: The gene is linked to insulin-resistance syndrome type A, hyperinsulinism due to INSR deficiency, Rabson-Mendenhall syndrome, Donohue syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19725701).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.84C>G	p.His28Gln	missense_variant	Exon 1 of 22	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.84C>G	p.His28Gln	missense_variant	Exon 1 of 21		NP_001073285.1
INSR	XM_011527988.3	c.84C>G	p.His28Gln	missense_variant	Exon 1 of 22		XP_011526290.2
INSR	XM_011527989.4	c.84C>G	p.His28Gln	missense_variant	Exon 1 of 21		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.84C>G	p.His28Gln	missense_variant	Exon 1 of 22	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.84C>G	p.His28Gln	missense_variant	Exon 1 of 21	1		ENSP00000342838.4
INSR	ENST00000598216.1	n.59C>G		non_coding_transcript_exon_variant	Exon 1 of 10	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1204468 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 589216

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 28 of the INSR protein (p.His28Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with INSR-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt INSR protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	18
DANN	Benign	0.85
DEOGEN2	Benign	0.40	.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.41	T;T
M_CAP	Pathogenic	0.73	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.32	N;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.46	N;N
REVEL	Benign	0.10
Sift	Benign	0.25	T;T
Sift4G	Benign	0.63	T;T
Polyphen		0.038	B;P
Vest4		0.15
MutPred		0.32		Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);
MVP		0.59
MPC		0.76
ClinPred		0.083	T
GERP RS		-0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.23
gMVP		0.37

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: chr19-7293819;