Genetic Variant NM_005544.3:c.1823C>A (chr2-226796916-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2PM5BP4_Moderate

The NM_005544.3(IRS1):c.1823C>A(p.Thr608Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

IRS1
NM_005544.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.733

Publications

18 publications found

Variant links:

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]

IRS1 links:

ENSG00000272622 (HGNC:):

ENSG00000272622 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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=0.24953333).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS1	NM_005544.3 link	c.1823C>A	p.Thr608Lys	missense_variant	Exon 1 of 2	ENST00000305123.6	NP_005535.1	P35568
IRS1	XM_047444223.1 link	c.1823C>A	p.Thr608Lys	missense_variant	Exon 1 of 2		XP_047300179.1
IRS1	XM_047444224.1 link	c.1823C>A	p.Thr608Lys	missense_variant	Exon 1 of 2		XP_047300180.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRS1	ENST00000305123.6 link	c.1823C>A	p.Thr608Lys	missense_variant	Exon 1 of 2	1	NM_005544.3	ENSP00000304895.4		P35568

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1393296

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

684818

African (AFR)

AF:

0.00

AC:

AN:

31652

American (AMR)

AF:

0.00

AC:

AN:

37074

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21312

East Asian (EAS)

AF:

0.00

AC:

AN:

39130

South Asian (SAS)

AF:

0.00

AC:

AN:

74586

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49900

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5412

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1076930

Other (OTH)

AF:

0.00

AC:

AN:

57300

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.066

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.33

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.60

M_CAP

Benign

0.019

MetaRNN

Benign

0.25

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.67

PhyloP100

0.73

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.25

REVEL

Benign

0.28

Sift

Benign

0.51

Sift4G

Benign

0.97

Polyphen

0.019

Vest4

0.64

MutPred

0.36

Gain of ubiquitination at T608 (P = 0.0018);

MVP

0.64

MPC

0.32

ClinPred

0.14

GERP RS

4.2

Varity_R

0.067

gMVP

0.46

Mutation Taster

=87/13

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over