2-226795333-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_005544.3(IRS1):c.3406G>A(p.Glu1136Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000192 in 1,613,394 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: IRS1 NM_005544.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 2.38

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009535074).
• BP6: Variant 2-226795333-C-T is Benign according to our data. Variant chr2-226795333-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1050448.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-226795333-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 73 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRS1	NM_005544.3	c.3406G>A	p.Glu1136Lys	missense_variant	1/2	ENST00000305123.6
IRS1	XM_047444223.1	c.3406G>A	p.Glu1136Lys	missense_variant	1/2
IRS1	XM_047444224.1	c.3406G>A	p.Glu1136Lys	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRS1	ENST00000305123.6	c.3406G>A	p.Glu1136Lys	missense_variant	1/2	1	NM_005544.3	P1

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 73 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000248 AC: 62 AN: 250132 Hom.: 0 AF XY: 0.000236 AC XY: 32 AN XY: 135416

Gnomad AFR exome AF: 0.00235

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000475

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000162 AC: 236 AN: 1461062 Hom.: 1 Cov.: 42 AF XY: 0.000155 AC XY: 113 AN XY: 726836

Gnomad4 AFR exome AF: 0.00281

Gnomad4 AMR exome AF: 0.000648

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.0000570

Gnomad4 NFE exome AF: 0.0000746

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152332 Hom.: 0 Cov.: 33 AF XY: 0.000510 AC XY: 38 AN XY: 74494

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000150 Hom.: 0

Bravo AF: 0.000521

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000214 AC: 26

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The IRS1 p.Glu1136Lys variant was identified in the literature somatically in a soft tissue sarcoma tumor from a cohort of 207 sarcoma patients (Barretina_2010_PMID:20601955). The variant was identified in dbSNP (ID: rs200142054) and LOVD 3.0 (classified as likely benign); the variant was not identified in ClinVar. The variant was identified in control databases in 73 of 281490 chromosomes at a frequency of 0.0002593 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 49 of 24882 chromosomes (freq: 0.001969), Latino in 16 of 35412 chromosomes (freq: 0.000452), Other in 2 of 7196 chromosomes (freq: 0.000278), East Asian in 1 of 19918 chromosomes (freq: 0.00005), European (Finnish) in 1 of 24510 chromosomes (freq: 0.000041), South Asian in 1 of 30604 chromosomes (freq: 0.000033) and European (non-Finnish) in 3 of 128634 chromosomes (freq: 0.000023), but was not observed in the Ashkenazi Jewish population. The p.Glu1136 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

IRS1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 10, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.36
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.033
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0095	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	0.78	N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.053
Sift	Benign	0.060	T
Sift4G	Benign	0.36	T
Polyphen		0.0040	B
Vest4		0.35
MVP		0.70
MPC		0.30
ClinPred		0.013	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.074
gMVP		0.22

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

LitVar

Other links and lift over

dbSNP: rs200142054; hg19: chr2-227660049;