2-226795160-C-T

Variant names:

• chr2-226795160-C-T
• rs140904930
• NM_005544.3:c.3579G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_005544.3(IRS1):​c.3579G>A​(p.Gln1193Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000294 in 1,613,832 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (2 hom.)
• Consequence: IRS1 NM_005544.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.751
• Publications: 0 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 2-226795160-C-T is Benign according to our data. Variant chr2-226795160-C-T is described in ClinVar as [Benign]. Clinvar id is 747307.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.751 with no splicing effect.
• BS2: High AC in GnomAd4 at 227 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS1	NM_005544.3	c.3579G>A	p.Gln1193Gln	synonymous_variant	Exon 1 of 2	ENST00000305123.6	NP_005535.1
IRS1	XM_047444223.1	c.3579G>A	p.Gln1193Gln	synonymous_variant	Exon 1 of 2		XP_047300179.1
IRS1	XM_047444224.1	c.3579G>A	p.Gln1193Gln	synonymous_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.3579G>A	p.Gln1193Gln	synonymous_variant	Exon 1 of 2	1	NM_005544.3	ENSP00000304895.4
IRS1	ENST00000498335.1	n.87G>A		non_coding_transcript_exon_variant	Exon 1 of 2	3
ENSG00000272622	ENST00000727652.1	n.166+320C>T		intron_variant	Intron 1 of 3
ENSG00000272622	ENST00000727654.1	n.71+217C>T		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes AF: 0.00151 AC: 229 AN: 152078 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00526

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000390 AC: 97 AN: 248848 AF XY: 0.000282

Gnomad AFR exome AF: 0.00570

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000169 AC: 247 AN: 1461636 Hom.: 2 Cov.: 41 AF XY: 0.000155 AC XY: 113 AN XY: 727116

African (AFR) AF: 0.00627 AC: 210 AN: 33480

American (AMR) AF: 0.000179 AC: 8 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53192

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111998

Other (OTH) AF: 0.000431 AC: 26 AN: 60388

GnomAD4 genome AF: 0.00149 AC: 227 AN: 152196 Hom.: 2 Cov.: 33 AF XY: 0.00149 AC XY: 111 AN XY: 74426

African (AFR) AF: 0.00520 AC: 216 AN: 41544

American (AMR) AF: 0.000393 AC: 6 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67998

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000998 Hom.: 1

Bravo AF: 0.00192

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.3
DANN	Benign	0.70
PhyloP100		0.75
Mutation Taster		=97/3	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: rs140904930; hg19: chr2-227659876;