Genetic Variant IRS1:p.Gly1212Val (chr2-226795104-C-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.58

Publications

1 publications found

Variant links:

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]

IRS1 links:

ENSG00000272622 (HGNC:):

ENSG00000272622 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 link	c.3635G>T	p.Gly1212Val	missense_variant	Exon 1 of 2	ENST00000305123.6	NP_005535.1	P35568
IRS1	XM_047444223.1 link	c.3635G>T	p.Gly1212Val	missense_variant	Exon 1 of 2		XP_047300179.1
IRS1	XM_047444224.1 link	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	UniProt
IRS1	ENST00000305123.6 link	c.3635G>T	p.Gly1212Val	missense_variant	Exon 1 of 2	1	NM_005544.3	ENSP00000304895.4	P35568
IRS1	ENST00000498335.1 link	n.143G>T		non_coding_transcript_exon_variant	Exon 1 of 2	3
ENSG00000272622	ENST00000727652.1 link	n.166+264C>A		intron_variant	Intron 1 of 3
ENSG00000272622	ENST00000727654.1 link	n.71+161C>A		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.00000730

AC:

AN:

136970

Hom.:

Cov.:

show subpopulations

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:

AN:

245822

AF XY:

0.00000744

show subpopulations

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:

AN:

1369536

Hom.:

Cov.:

AF XY:

0.00000438

AC XY:

AN XY:

684208

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31622

American (AMR)

AF:

0.00

AC:

AN:

44124

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25088

East Asian (EAS)

AF:

0.00

AC:

AN:

38084

South Asian (SAS)

AF:

0.00

AC:

AN:

84460

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5514

European-Non Finnish (NFE)

AF:

0.00000677

AC:

AN:

1033226

Other (OTH)

AF:

0.00

AC:

AN:

56798

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000730

AC:

AN:

136970

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

65928

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

37106

American (AMR)

AF:

0.00

AC:

AN:

13418

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3308

East Asian (EAS)

AF:

0.00

AC:

AN:

4162

South Asian (SAS)

AF:

0.00

AC:

AN:

3798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8528

Middle Eastern (MID)

AF:

0.00

AC:

AN:

296

European-Non Finnish (NFE)

AF:

0.0000157

AC:

AN:

63632

Other (OTH)

AF:

0.00

AC:

AN:

1874

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000565

Hom.:

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

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.55

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.68

M_CAP

Benign

0.019

MetaRNN

Benign

0.29

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.8

PhyloP100

1.6

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.13

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.012

Polyphen

0.30

Vest4

0.39

MutPred

0.34

Gain of relative solvent accessibility (P = 0.09);

MVP

0.77

MPC

0.48

ClinPred

0.12

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

(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.

2-226795104-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over