chr2-226795474-G-C

Variant names:

• chr2-226795474-G-C
• rs781408207
• NM_005544.3:c.3265C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_005544.3(IRS1):​c.3265C>G​(p.Arg1089Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R1089C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: IRS1 NM_005544.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.87
• Publications: 0 publications found

Genes affected

IRS1 (HGNC:6125): (insulin receptor substrate 1) This gene encodes a protein which is phosphorylated by insulin receptor tyrosine kinase. Mutations in this gene are associated with type II diabetes and susceptibility to insulin resistance. [provided by RefSeq, Nov 2009]

ENSG00000272622 (HGNC:):

ACMG classification

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

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.871
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS1	NM_005544.3	c.3265C>G	p.Arg1089Gly	missense_variant	Exon 1 of 2	ENST00000305123.6	NP_005535.1
IRS1	XM_047444223.1	c.3265C>G	p.Arg1089Gly	missense_variant	Exon 1 of 2		XP_047300179.1
IRS1	XM_047444224.1	c.3265C>G	p.Arg1089Gly	missense_variant	Exon 1 of 2		XP_047300180.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRS1	ENST00000305123.6	c.3265C>G	p.Arg1089Gly	missense_variant	Exon 1 of 2	1	NM_005544.3	ENSP00000304895.4
ENSG00000272622	ENST00000727652.1	n.166+634G>C		intron_variant	Intron 1 of 3
ENSG00000272622	ENST00000727654.1	n.71+531G>C		intron_variant	Intron 1 of 3
IRS1	ENST00000498335.1	n.-228C>G		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461226 Hom.: 0 Cov.: 42 AF XY: 0.00000550 AC XY: 4 AN XY: 726934

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52764

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Benign	0.69	N
PhyloP100		3.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.53		Loss of MoRF binding (P = 0.0057);
MVP		0.97
MPC		1.1
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.71
gMVP		0.63
Mutation Taster		=64/36	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: rs781408207; hg19: chr2-227660190; COSMIC: COSV59337840; COSMIC: COSV59337840;