chr2-226795498-G-A

Variant names:

• chr2-226795498-G-A
• rs200670773
• NM_005544.3:c.3241C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005544.3(IRS1):​c.3241C>T​(p.Arg1081Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,613,478 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1081H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: IRS1 NM_005544.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.10
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15430495).
• BS2: High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS1	NM_005544.3	c.3241C>T	p.Arg1081Cys	missense_variant	Exon 1 of 2	ENST00000305123.6	NP_005535.1
IRS1	XM_047444223.1	c.3241C>T	p.Arg1081Cys	missense_variant	Exon 1 of 2		XP_047300179.1
IRS1	XM_047444224.1	c.3241C>T	p.Arg1081Cys	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.3241C>T	p.Arg1081Cys	missense_variant	Exon 1 of 2	1	NM_005544.3	ENSP00000304895.4
ENSG00000272622	ENST00000727652.1	n.166+658G>A		intron_variant	Intron 1 of 3
ENSG00000272622	ENST00000727654.1	n.71+555G>A		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

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: 0.00318

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000440 AC: 11 AN: 250066 AF XY: 0.0000517

Gnomad AFR exome AF: 0.000123

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: 0.0000711

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000315 AC: 46 AN: 1461188 Hom.: 0 Cov.: 41 AF XY: 0.0000344 AC XY: 25 AN XY: 726924

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

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: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52728

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

European-Non Finnish (NFE) AF: 0.0000369 AC: 41 AN: 1112002

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

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152290 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74460

African (AFR) AF: 0.0000722 AC: 3 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000302

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3241C>T (p.R1081C) alteration is located in exon 1 (coding exon 1) of the IRS1 gene. This alteration results from a C to T substitution at nucleotide position 3241, causing the arginine (R) at amino acid position 1081 to be replaced by a cysteine (C). 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	0.073
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.55	N
PhyloP100		3.1
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.13
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.019	D
Polyphen		0.98	D
Vest4		0.15
MVP		0.73
MPC		0.36
ClinPred		0.081	T
GERP RS		2.4
Varity_R		0.12
gMVP		0.22
Mutation Taster		=92/8	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: rs200670773; hg19: chr2-227660214; COSMIC: COSV59336734; COSMIC: COSV59336734;