rs2229431

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000208.4(INSR):c.2595C>T(p.Asn865Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0577 in 1,614,032 control chromosomes in the GnomAD database, including 3,258 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.082 ( 715 hom., cov: 31)

Exomes 𝑓: 0.055 ( 2543 hom. )

Consequence

INSR
NM_000208.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.753

Publications

21 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 19-7141764-G-A is Benign according to our data. Variant chr19-7141764-G-A is described in ClinVar as Benign. ClinVar VariationId is 330454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.753 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4 link	c.2595C>T	p.Asn865Asn	synonymous_variant	Exon 13 of 22	ENST00000302850.10	NP_000199.2	P06213-1
INSR	NM_001079817.3 link	c.2559C>T	p.Asn853Asn	synonymous_variant	Exon 12 of 21		NP_001073285.1	P06213-2
INSR	XM_011527988.3 link	c.2595C>T	p.Asn865Asn	synonymous_variant	Exon 13 of 22		XP_011526290.2
INSR	XM_011527989.4 link	c.2559C>T	p.Asn853Asn	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.2595C>T	p.Asn865Asn	synonymous_variant	Exon 13 of 22	1	NM_000208.4	ENSP00000303830.4	P06213-1
INSR	ENST00000341500.9 link	c.2559C>T	p.Asn853Asn	synonymous_variant	Exon 12 of 21	1		ENSP00000342838.4	P06213-2
INSR	ENST00000597211.1 link	n.278C>T		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.0822

AC:

12499

AN:

152112

Hom.:

713

Cov.:

show subpopulations

Gnomad AFR

AF:

0.155

Gnomad AMI

AF:

0.0526

Gnomad AMR

AF:

0.0542

Gnomad ASJ

AF:

0.0735

Gnomad EAS

AF:

0.0781

Gnomad SAS

AF:

0.0435

Gnomad FIN

AF:

0.0730

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0493

Gnomad OTH

AF:

0.0860

GnomAD2 exomes

AF:

0.0611

AC:

15360

AN:

251468

AF XY:

0.0586

show subpopulations

Gnomad AFR exome

AF:

0.157

Gnomad AMR exome

AF:

0.0604

Gnomad ASJ exome

AF:

0.0785

Gnomad EAS exome

AF:

0.0688

Gnomad FIN exome

AF:

0.0703

Gnomad NFE exome

AF:

0.0476

Gnomad OTH exome

AF:

0.0580

GnomAD4 exome

AF:

0.0552

AC:

80646

AN:

1461802

Hom.:

2543

Cov.:

AF XY:

0.0545

AC XY:

39658

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.156

AC:

5221

AN:

33470

American (AMR)

AF:

0.0597

AC:

2669

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0782

AC:

2045

AN:

26136

East Asian (EAS)

AF:

0.0932

AC:

3701

AN:

39700

South Asian (SAS)

AF:

0.0455

AC:

3926

AN:

86258

European-Finnish (FIN)

AF:

0.0687

AC:

3670

AN:

53418

Middle Eastern (MID)

AF:

0.0659

AC:

380

AN:

5768

European-Non Finnish (NFE)

AF:

0.0499

AC:

55482

AN:

1111932

Other (OTH)

AF:

0.0588

AC:

3552

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

4535

9070

13605

18140

22675

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2228

4456

6684

8912

11140

<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:

0.0822

AC:

12514

AN:

152230

Hom.:

715

Cov.:

AF XY:

0.0832

AC XY:

6195

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.155

AC:

6450

AN:

41544

American (AMR)

AF:

0.0543

AC:

830

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0735

AC:

255

AN:

3468

East Asian (EAS)

AF:

0.0783

AC:

404

AN:

5162

South Asian (SAS)

AF:

0.0436

AC:

210

AN:

4820

European-Finnish (FIN)

AF:

0.0730

AC:

774

AN:

10604

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0492

AC:

3348

AN:

68020

Other (OTH)

AF:

0.0851

AC:

180

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

569

1138

1706

2275

2844

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

264

396

528

660

<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:

0.0600

Hom.:

1473

Bravo

AF:

0.0858

Asia WGS

AF:

0.0570

AC:

201

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jun 10, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Insulin-resistant diabetes mellitus AND acanthosis nigricans

Benign:1

Jan 12, 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 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Leprechaunism syndrome

Benign:1

Jan 12, 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

-0.80

CADD

Benign

1.0

(source)

DANN

Benign

0.54

PhyloP100

-0.75

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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