rs104893642

chr2-226796916-G-Achr2-226796916-G-Cchr2-226796916-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM5 BP4

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. 14/21 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

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 Uncertain_significance. Variant got 1 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 id is 29762.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2947556).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRS1	NM_005544.3	c.1823C>T	p.Thr608Met	missense_variant	1/2	ENST00000305123.6
IRS1	XM_047444223.1	c.1823C>T	p.Thr608Met	missense_variant	1/2
IRS1	XM_047444224.1	c.1823C>T	p.Thr608Met	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRS1	ENST00000305123.6	c.1823C>T	p.Thr608Met	missense_variant	1/2	1	NM_005544.3	P1

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

GnomAD3 exomes AF: 0.0000151 AC: 3 AN: 198034 Hom.: 0 AF XY: 0.0000192 AC XY: 2 AN XY: 104386

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000270

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000200

Gnomad4 NFE exome AF: 0.0000269

Gnomad4 OTH exome AF: 0.0000349

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

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

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 v4.3

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
MutationTaster	Benign	0.88	N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs104893642; hg19: chr2-227661632;