rs104893642

Variant names:

• chr2-226796916-G-A
• rs104893642
• NM_005544.3:c.1823C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-226796916-G-A
• chr2-226796916-G-C
• chr2-226796916-G-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM5 BP4 BS2

The NM_005544.3(IRS1):​c.1823C>T​(p.Thr608Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,545,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T608R) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: IRS1 NM_005544.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.733
• Publications: 18 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: Likely_benign. The variant received -3 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-226796916-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 29762.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2947556).
• BS2: High AC in GnomAdExome4 at 33 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRS1	NM_005544.3	MANE Select	c.1823C>T	p.Thr608Met	missense	Exon 1 of 2	NP_005535.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRS1	ENST00000305123.6	TSL:1 MANE Select	c.1823C>T	p.Thr608Met	missense	Exon 1 of 2	ENSP00000304895.4
	ENSG00000272622	ENST00000727652.1		n.166+2076G>A		intron	N/A
	ENSG00000272622	ENST00000727653.1		n.348+357G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000151 AC: 3 AN: 198034 AF XY: 0.0000192

Gnomad AFR exome AF: 0.0000639

Gnomad AMR exome AF: 0.0000363

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000108

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000237 AC: 33 AN: 1393298 Hom.: 0 Cov.: 37 AF XY: 0.0000277 AC XY: 19 AN XY: 684818

African (AFR) AF: 0.00 AC: 0 AN: 31652

American (AMR) AF: 0.0000270 AC: 1 AN: 37074

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21312

East Asian (EAS) AF: 0.00 AC: 0 AN: 39130

South Asian (SAS) AF: 0.00 AC: 0 AN: 74586

European-Finnish (FIN) AF: 0.0000200 AC: 1 AN: 49902

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5412

European-Non Finnish (NFE) AF: 0.0000269 AC: 29 AN: 1076930

Other (OTH) AF: 0.0000349 AC: 2 AN: 57300

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152174 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74340

African (AFR) AF: 0.0000241 AC: 1 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000167 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.040
Eigen_PC	Benign	-0.013
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.73
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.14
Sift	Benign	0.046	D
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.47
MVP		0.78
MPC		0.59
ClinPred		0.14	T
GERP RS		4.2
Varity_R		0.045
gMVP		0.35
Mutation Taster		=88/12	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: rs104893642; hg19: chr2-227661632;