2-226790674-G-C

Variant names:

• chr2-226790674-G-C
• rs2288586
• NM_005544.3:c.*21+4315C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005544.3(IRS1):​c.*21+4315C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 152,176 control chromosomes in the GnomAD database, including 1,102 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 0.11 (1102 hom., cov: 32)
• Consequence: IRS1 NM_005544.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.622
• Publications: 9 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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.234 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS1	NM_005544.3	c.*21+4315C>G		intron_variant	Intron 1 of 1	ENST00000305123.6	NP_005535.1
IRS1	XM_047444223.1	c.*1733C>G		3_prime_UTR_variant	Exon 2 of 2		XP_047300179.1
IRS1	XM_047444224.1	c.*21+4315C>G		intron_variant	Intron 1 of 1		XP_047300180.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRS1	ENST00000305123.6	c.*21+4315C>G		intron_variant	Intron 1 of 1	1	NM_005544.3	ENSP00000304895.4

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16199 AN: 152058 Hom.: 1100 Cov.: 32

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.218

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.0314

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.0678

Gnomad OTH AF: 0.111

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.107 AC: 16233 AN: 152176 Hom.: 1102 Cov.: 32 AF XY: 0.109 AC XY: 8097 AN XY: 74390

African (AFR) AF: 0.142 AC: 5897 AN: 41508

American (AMR) AF: 0.148 AC: 2264 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 481 AN: 3462

East Asian (EAS) AF: 0.218 AC: 1126 AN: 5164

South Asian (SAS) AF: 0.245 AC: 1181 AN: 4812

European-Finnish (FIN) AF: 0.0314 AC: 333 AN: 10606

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.0678 AC: 4614 AN: 68010

Other (OTH) AF: 0.117 AC: 247 AN: 2112

Alfa AF: 0.0282 Hom.: 21

Bravo AF: 0.116

Asia WGS AF: 0.231 AC: 801 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.6
DANN	Benign	0.71
PhyloP100		0.62
Mutation Taster		=100/0	polymorphism (auto)

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: rs2288586; hg19: chr2-227655390;