chr2-226799185-C-T

Position:

• chr2-226799185-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005544.3(IRS1):​c.-447G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0502 in 1,105,064 control chromosomes in the GnomAD database, including 4,613 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.13 (2609 hom., cov: 32)
  • Exomes 𝑓: 0.038 (2004 hom.)
• Consequence: IRS1 NM_005544.3 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.648

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.335 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRS1	NM_005544.3	c.-447G>A		5_prime_UTR_variant	1/2	ENST00000305123.6	NP_005535.1
IRS1	XM_047444223.1	c.-447G>A		5_prime_UTR_variant	1/2		XP_047300179.1
IRS1	XM_047444224.1	c.-447G>A		5_prime_UTR_variant	1/2		XP_047300180.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRS1	ENST00000305123.6	c.-447G>A		5_prime_UTR_variant	1/2	1	NM_005544.3	ENSP00000304895	P1

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19549 AN: 151852 Hom.: 2603 Cov.: 32

Gnomad AFR AF: 0.340

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0910

Gnomad ASJ AF: 0.0665

Gnomad EAS AF: 0.0938

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.0368

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0307

Gnomad OTH AF: 0.109

GnomAD4 exome AF: 0.0377 AC: 35928 AN: 953094 Hom.: 2004 Cov.: 34 AF XY: 0.0390 AC XY: 17515 AN XY: 449478

Gnomad4 AFR exome AF: 0.368

Gnomad4 AMR exome AF: 0.0679

Gnomad4 ASJ exome AF: 0.0550

Gnomad4 EAS exome AF: 0.0728

Gnomad4 SAS exome AF: 0.128

Gnomad4 FIN exome AF: 0.0372

Gnomad4 NFE exome AF: 0.0254

Gnomad4 OTH exome AF: 0.0573

GnomAD4 genome AF: 0.129 AC: 19579 AN: 151970 Hom.: 2609 Cov.: 32 AF XY: 0.128 AC XY: 9542 AN XY: 74284

Gnomad4 AFR AF: 0.339

Gnomad4 AMR AF: 0.0914

Gnomad4 ASJ AF: 0.0665

Gnomad4 EAS AF: 0.0944

Gnomad4 SAS AF: 0.141

Gnomad4 FIN AF: 0.0368

Gnomad4 NFE AF: 0.0306

Gnomad4 OTH AF: 0.109

Alfa AF: 0.0955 Hom.: 656

Bravo AF: 0.141

Asia WGS AF: 0.124 AC: 432 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	18
DANN	Benign	0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs13306465; hg19: chr2-227663901;