NM_005544.3:c.1534G>C

Variant names:

• chr2-226797205-C-G
• rs1801276
• NM_005544.3:c.1534G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005544.3(IRS1):​c.1534G>C​(p.Ala512Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0189 in 1,613,794 control chromosomes in the GnomAD database, including 354 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (27 hom., cov: 33)
  • Exomes 𝑓: 0.020 (327 hom.)
• Consequence: IRS1 NM_005544.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.986
• Publications: 31 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026758611).
• BP6: Variant 2-226797205-C-G is Benign according to our data. Variant chr2-226797205-C-G is described in ClinVar as Benign. ClinVar VariationId is 522186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0133 (2023/152332) while in subpopulation NFE AF = 0.0221 (1505/68020). AF 95% confidence interval is 0.0212. There are 27 homozygotes in GnomAd4. There are 948 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2023 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005544.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRS1	NM_005544.3	MANE Select	c.1534G>C	p.Ala512Pro	missense	Exon 1 of 2	NP_005535.1	P35568

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRS1	ENST00000305123.6	TSL:1 MANE Select	c.1534G>C	p.Ala512Pro	missense	Exon 1 of 2	ENSP00000304895.4	P35568
	IRS1	ENST00000918829.1		c.1534G>C	p.Ala512Pro	missense	Exon 1 of 2	ENSP00000588888.1
	ENSG00000272622	ENST00000727652.1		n.166+2365C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2023 AN: 152214 Hom.: 27 Cov.: 33

Gnomad AFR AF: 0.00323

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00464

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00786

Gnomad FIN AF: 0.0213

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0221

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.0140 AC: 3505 AN: 250798 AF XY: 0.0144

Gnomad AFR exome AF: 0.00353

Gnomad AMR exome AF: 0.00463

Gnomad ASJ exome AF: 0.00517

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0211

Gnomad NFE exome AF: 0.0217

Gnomad OTH exome AF: 0.0147

GnomAD4 exome AF: 0.0195 AC: 28529 AN: 1461462 Hom.: 327 Cov.: 37 AF XY: 0.0194 AC XY: 14092 AN XY: 727020

African (AFR) AF: 0.00278 AC: 93 AN: 33480

American (AMR) AF: 0.00479 AC: 214 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00593 AC: 155 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00768 AC: 662 AN: 86242

European-Finnish (FIN) AF: 0.0213 AC: 1132 AN: 53052

Middle Eastern (MID) AF: 0.00433 AC: 25 AN: 5768

European-Non Finnish (NFE) AF: 0.0227 AC: 25266 AN: 1111982

Other (OTH) AF: 0.0162 AC: 981 AN: 60388

GnomAD4 genome AF: 0.0133 AC: 2023 AN: 152332 Hom.: 27 Cov.: 33 AF XY: 0.0127 AC XY: 948 AN XY: 74486

African (AFR) AF: 0.00322 AC: 134 AN: 41588

American (AMR) AF: 0.00464 AC: 71 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00518 AC: 18 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5170

South Asian (SAS) AF: 0.00787 AC: 38 AN: 4828

European-Finnish (FIN) AF: 0.0213 AC: 226 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0221 AC: 1505 AN: 68020

Other (OTH) AF: 0.0109 AC: 23 AN: 2114

Alfa AF: 0.0194 Hom.: 10

Bravo AF: 0.0112

TwinsUK AF: 0.0191 AC: 71

ALSPAC AF: 0.0192 AC: 74

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.0203 AC: 175

ExAC AF: 0.0142 AC: 1728

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0218

EpiControl AF: 0.0193

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Type 2 diabetes mellitus (2)
-	-	1	IRS1-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	16
DANN	Benign	0.89
DEOGEN2	Benign	0.38	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.99
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.076
Sift	Benign	0.27	T
Sift4G	Benign	0.33	T
Polyphen		0.0060	B
Vest4		0.069
MPC		0.39
ClinPred		0.0020	T
GERP RS		4.5
Varity_R		0.14
gMVP		0.45
Mutation Taster		=83/17	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: rs1801276; hg19: chr2-227661921;