rs2229432

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_000208.4(INSR):c.2643C>T(p.Ile881Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00931 in 1,614,070 control chromosomes in the GnomAD database, including 163 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 49 hom., cov: 31)

Exomes 𝑓: 0.0084 ( 114 hom. )

Consequence

INSR
NM_000208.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.12

Publications

7 publications found

Variant links:

Genes affected

INSR (HGNC:6091): (insulin receptor) This gene encodes a member of the receptor tyrosine kinase family of proteins. The encoded preproprotein is proteolytically processed to generate alpha and beta subunits that form a heterotetrameric receptor. Binding of insulin or other ligands to this receptor activates the insulin signaling pathway, which regulates glucose uptake and release, as well as the synthesis and storage of carbohydrates, lipids and protein. Mutations in this gene underlie the inherited severe insulin resistance syndromes including type A insulin resistance syndrome, Donohue syndrome and Rabson-Mendenhall syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

INSR Gene-Disease associations (from GenCC):

insulin-resistance syndrome type A
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P
Donohue syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
hyperinsulinism due to INSR deficiency
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, Ambry Genetics
Rabson-Mendenhall syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

INSR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.29).

BP6

Variant 19-7141716-G-A is Benign according to our data. Variant chr19-7141716-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 330453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.12 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0184 (2808/152274) while in subpopulation AFR AF = 0.0437 (1818/41564). AF 95% confidence interval is 0.0421. There are 49 homozygotes in GnomAd4. There are 1369 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 49 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4 link	c.2643C>T	p.Ile881Ile	synonymous_variant	Exon 13 of 22	ENST00000302850.10	NP_000199.2	P06213-1
INSR	NM_001079817.3 link	c.2607C>T	p.Ile869Ile	synonymous_variant	Exon 12 of 21		NP_001073285.1	P06213-2
INSR	XM_011527988.3 link	c.2643C>T	p.Ile881Ile	synonymous_variant	Exon 13 of 22		XP_011526290.2
INSR	XM_011527989.4 link	c.2607C>T	p.Ile869Ile	synonymous_variant	Exon 12 of 21		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
INSR	ENST00000302850.10 link	c.2643C>T	p.Ile881Ile	synonymous_variant	Exon 13 of 22	1	NM_000208.4	ENSP00000303830.4	P06213-1
INSR	ENST00000341500.9 link	c.2607C>T	p.Ile869Ile	synonymous_variant	Exon 12 of 21	1		ENSP00000342838.4	P06213-2
INSR	ENST00000597211.1 link	n.326C>T		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.0183

AC:

2792

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0434

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00720

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.0417

Gnomad SAS

AF:

0.00415

Gnomad FIN

AF:

0.00960

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00664

Gnomad OTH

AF:

0.0163

GnomAD2 exomes

AF:

0.0113

AC:

2837

AN:

251482

AF XY:

0.0100

show subpopulations

Gnomad AFR exome

AF:

0.0457

Gnomad AMR exome

AF:

0.00437

Gnomad ASJ exome

AF:

0.0118

Gnomad EAS exome

AF:

0.0391

Gnomad FIN exome

AF:

0.0101

Gnomad NFE exome

AF:

0.00672

Gnomad OTH exome

AF:

0.00978

GnomAD4 exome

AF:

0.00836

AC:

12215

AN:

1461796

Hom.:

114

Cov.:

AF XY:

0.00796

AC XY:

5786

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.0427

AC:

1428

AN:

33478

American (AMR)

AF:

0.00467

AC:

209

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0130

AC:

341

AN:

26136

East Asian (EAS)

AF:

0.0418

AC:

1658

AN:

39700

South Asian (SAS)

AF:

0.00223

AC:

192

AN:

86254

European-Finnish (FIN)

AF:

0.0105

AC:

562

AN:

53418

Middle Eastern (MID)

AF:

0.00971

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00640

AC:

7113

AN:

1111924

Other (OTH)

AF:

0.0109

AC:

656

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

705

1410

2115

2820

3525

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

324

648

972

1296

1620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0184

AC:

2808

AN:

152274

Hom.:

Cov.:

AF XY:

0.0184

AC XY:

1369

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0437

AC:

1818

AN:

41564

American (AMR)

AF:

0.00719

AC:

110

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0153

AC:

AN:

3472

East Asian (EAS)

AF:

0.0415

AC:

214

AN:

5162

South Asian (SAS)

AF:

0.00415

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00960

AC:

102

AN:

10622

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00664

AC:

452

AN:

68028

Other (OTH)

AF:

0.0161

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

136

272

409

545

681

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0114

Hom.:

Bravo

AF:

0.0200

Asia WGS

AF:

0.0230

AC:

AN:

3478

EpiCase

AF:

0.00523

EpiControl

AF:

0.00510

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Insulin-resistant diabetes mellitus AND acanthosis nigricans

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Rabson-Mendenhall syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hyperinsulinism due to INSR deficiency

Benign:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

Potent mutations in INSR gene can lead to insulin resistance, which presents as impaired glucose tolerance, early onset type 2 diabetes, post prandial hyperglycemia and increased insulin requirement in type 1 diabetes. These mutations in INSR gene can also predispose to coronary artery disease, metabolic syndrome, polycystic ovarian disease and non alcoholic fatty liver disease.However, the role of this particular variant rs2229432 with early onset diabetes mellitus is yet to be ascertained. -

Leprechaunism syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.29

CADD

Benign

0.35

(source)

DANN

Benign

0.78

PhyloP100

-1.1

Mutation Taster

=100/0

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over