2-226795099-C-G

Variant names:

• chr2-226795099-C-G
• NM_005544.3:c.3640G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005544.3(IRS1):​c.3640G>C​(p.Gly1214Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1214S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 24)
• Consequence: IRS1 NM_005544.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.692

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07274306).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS1	NM_005544.3	c.3640G>C	p.Gly1214Arg	missense_variant	Exon 1 of 2	ENST00000305123.6	NP_005535.1
IRS1	XM_047444223.1	c.3640G>C	p.Gly1214Arg	missense_variant	Exon 1 of 2		XP_047300179.1
IRS1	XM_047444224.1	c.3640G>C	p.Gly1214Arg	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	c.3640G>C	p.Gly1214Arg	missense_variant	Exon 1 of 2	1	NM_005544.3	ENSP00000304895.4
IRS1	ENST00000498335.1	n.148G>C		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 43

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3640G>C (p.G1214R) alteration is located in exon 1 (coding exon 1) of the IRS1 gene. This alteration results from a G to C substitution at nucleotide position 3640, causing the glycine (G) at amino acid position 1214 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	13
DANN	Benign	0.87
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.038
Sift	Benign	0.18	T
Sift4G	Uncertain	0.022	D
Polyphen		0.0010	B
Vest4		0.054
MutPred		0.17		Loss of catalytic residue at P1210 (P = 0.0829);
MVP		0.53
MPC		0.32
ClinPred		0.055	T
GERP RS		-1.5
Varity_R		0.085
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-227659815;