chr2-226795104-C-A

Variant names:

• chr2-226795104-C-A
• rs973649983
• NM_005544.3:c.3635G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_005544.3(IRS1):​c.3635G>T​(p.Gly1212Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000531 in 1,506,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. G1212D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000073 (0 hom., cov: 25)
  • Exomes 𝑓: 0.0000051 (0 hom.)
• Consequence: IRS1 NM_005544.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.58
• Publications: 1 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28836808).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS1	NM_005544.3	c.3635G>T	p.Gly1212Val	missense_variant	Exon 1 of 2	ENST00000305123.6	NP_005535.1
IRS1	XM_047444223.1	c.3635G>T	p.Gly1212Val	missense_variant	Exon 1 of 2		XP_047300179.1
IRS1	XM_047444224.1	c.3635G>T	p.Gly1212Val	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.3635G>T	p.Gly1212Val	missense_variant	Exon 1 of 2	1	NM_005544.3	ENSP00000304895.4
IRS1	ENST00000498335.1	n.143G>T		non_coding_transcript_exon_variant	Exon 1 of 2	3
ENSG00000272622	ENST00000727652.1	n.166+264C>A		intron_variant	Intron 1 of 3
ENSG00000272622	ENST00000727654.1	n.71+161C>A		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes AF: 0.00000730 AC: 1 AN: 136970 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000157

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000814 AC: 2 AN: 245822 AF XY: 0.00000744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000511 AC: 7 AN: 1369536 Hom.: 0 Cov.: 44 AF XY: 0.00000438 AC XY: 3 AN XY: 684208

African (AFR) AF: 0.00 AC: 0 AN: 31622

American (AMR) AF: 0.00 AC: 0 AN: 44124

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25088

East Asian (EAS) AF: 0.00 AC: 0 AN: 38084

South Asian (SAS) AF: 0.00 AC: 0 AN: 84460

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5514

European-Non Finnish (NFE) AF: 0.00000677 AC: 7 AN: 1033226

Other (OTH) AF: 0.00 AC: 0 AN: 56798

GnomAD4 genome AF: 0.00000730 AC: 1 AN: 136970 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 65928

African (AFR) AF: 0.00 AC: 0 AN: 37106

American (AMR) AF: 0.00 AC: 0 AN: 13418

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3308

East Asian (EAS) AF: 0.00 AC: 0 AN: 4162

South Asian (SAS) AF: 0.00 AC: 0 AN: 3798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 296

European-Non Finnish (NFE) AF: 0.0000157 AC: 1 AN: 63632

Other (OTH) AF: 0.00 AC: 0 AN: 1874

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.6
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.13
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.012	D
Polyphen		0.30	B
Vest4		0.39
MutPred		0.34		Gain of relative solvent accessibility (P = 0.09);
MVP		0.77
MPC		0.48
ClinPred		0.12	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.40
Mutation Taster		=78/22	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: rs973649983; hg19: chr2-227659820;