chr2-226797205-C-G

Position:

• chr2-226797205-C-G

Variant summary

Our verdict is Benign. Variant got -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. 15/20 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

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 Benign. Variant got -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 id is 522186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-226797205-C-G is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2023 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRS1	NM_005544.3	c.1534G>C	p.Ala512Pro	missense_variant	1/2	ENST00000305123.6	NP_005535.1
IRS1	XM_047444223.1	c.1534G>C	p.Ala512Pro	missense_variant	1/2		XP_047300179.1
IRS1	XM_047444224.1	c.1534G>C	p.Ala512Pro	missense_variant	1/2		XP_047300180.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRS1	ENST00000305123.6	c.1534G>C	p.Ala512Pro	missense_variant	1/2	1	NM_005544.3	ENSP00000304895.4

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

GnomAD3 exomes AF: 0.0140 AC: 3505 AN: 250798 Hom.: 39 AF XY: 0.0144 AC XY: 1958 AN XY: 135696

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 SAS exome AF: 0.00758

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

Gnomad4 AFR exome AF: 0.00278

Gnomad4 AMR exome AF: 0.00479

Gnomad4 ASJ exome AF: 0.00593

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00768

Gnomad4 FIN exome AF: 0.0213

Gnomad4 NFE exome AF: 0.0227

Gnomad4 OTH exome AF: 0.0162

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

Gnomad4 AFR AF: 0.00322

Gnomad4 AMR AF: 0.00464

Gnomad4 ASJ AF: 0.00518

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00787

Gnomad4 FIN AF: 0.0213

Gnomad4 NFE AF: 0.0221

Gnomad4 OTH AF: 0.0109

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

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Type 2 diabetes mellitus Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Dec 16, 2016	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

IRS1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

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
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

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: rs1801276; hg19: chr2-227661921;