rs2963

Variant names:

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.1918C>T(p.Leu640Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0933 in 1,611,114 control chromosomes in the GnomAD database, including 9,582 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1698 hom., cov: 31)

Exomes 𝑓: 0.090 ( 7884 hom. )

Consequence

INSR
NM_000208.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0530

Publications

25 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=-0.79).

BP6

Variant 19-7163143-G-A is Benign according to our data. Variant chr19-7163143-G-A is described in ClinVar as Benign. ClinVar VariationId is 330468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.053 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.241 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4 link	c.1918C>T	p.Leu640Leu	synonymous_variant	Exon 9 of 22	ENST00000302850.10	NP_000199.2	P06213-1
INSR	NM_001079817.3 link	c.1918C>T	p.Leu640Leu	synonymous_variant	Exon 9 of 21		NP_001073285.1	P06213-2
INSR	XM_011527988.3 link	c.1918C>T	p.Leu640Leu	synonymous_variant	Exon 9 of 22		XP_011526290.2
INSR	XM_011527989.4 link	c.1918C>T	p.Leu640Leu	synonymous_variant	Exon 9 of 21		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
INSR	ENST00000302850.10 link	c.1918C>T	p.Leu640Leu	synonymous_variant	Exon 9 of 22	1	NM_000208.4	ENSP00000303830.4	P06213-1
INSR	ENST00000341500.9 link	c.1918C>T	p.Leu640Leu	synonymous_variant	Exon 9 of 21	1		ENSP00000342838.4	P06213-2
INSR	ENST00000598216.1 link	n.1893C>T		non_coding_transcript_exon_variant	Exon 9 of 10	1
INSR	ENST00000600492.1 link	c.319C>T	p.Leu107Leu	synonymous_variant	Exon 3 of 4	5		ENSP00000473170.1	M0R3E6

Frequencies

GnomAD3 genomes

AF:

0.126

AC:

19121

AN:

151966

Hom.:

1691

Cov.:

show subpopulations

Gnomad AFR

AF:

0.245

Gnomad AMI

AF:

0.157

Gnomad AMR

AF:

0.0827

Gnomad ASJ

AF:

0.0461

Gnomad EAS

AF:

0.0283

Gnomad SAS

AF:

0.245

Gnomad FIN

AF:

0.0389

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.0797

Gnomad OTH

AF:

0.119

GnomAD2 exomes

AF:

0.0984

AC:

24751

AN:

251456

AF XY:

0.104

show subpopulations

Gnomad AFR exome

AF:

0.244

Gnomad AMR exome

AF:

0.0601

Gnomad ASJ exome

AF:

0.0490

Gnomad EAS exome

AF:

0.0258

Gnomad FIN exome

AF:

0.0449

Gnomad NFE exome

AF:

0.0775

Gnomad OTH exome

AF:

0.0916

GnomAD4 exome

AF:

0.0899

AC:

131098

AN:

1459030

Hom.:

7884

Cov.:

AF XY:

0.0938

AC XY:

68101

AN XY:

725942

show subpopulations

African (AFR)

AF:

0.247

AC:

8232

AN:

33340

American (AMR)

AF:

0.0634

AC:

2836

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0481

AC:

1256

AN:

26128

East Asian (EAS)

AF:

0.0304

AC:

1208

AN:

39690

South Asian (SAS)

AF:

0.234

AC:

20181

AN:

86150

European-Finnish (FIN)

AF:

0.0454

AC:

2424

AN:

53414

Middle Eastern (MID)

AF:

0.114

AC:

653

AN:

5742

European-Non Finnish (NFE)

AF:

0.0797

AC:

88478

AN:

1109562

Other (OTH)

AF:

0.0967

AC:

5830

AN:

60288

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.411

Heterozygous variant carriers

6477

12953

19430

25906

32383

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3464

6928

10392

13856

17320

<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:

0.126

AC:

19165

AN:

152084

Hom.:

1698

Cov.:

AF XY:

0.125

AC XY:

9318

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.245

AC:

10164

AN:

41472

American (AMR)

AF:

0.0826

AC:

1260

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.0461

AC:

160

AN:

3470

East Asian (EAS)

AF:

0.0282

AC:

146

AN:

5178

South Asian (SAS)

AF:

0.244

AC:

1175

AN:

4810

European-Finnish (FIN)

AF:

0.0389

AC:

412

AN:

10604

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0797

AC:

5418

AN:

67974

Other (OTH)

AF:

0.123

AC:

260

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

794

1588

2381

3175

3969

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

210

420

630

840

1050

<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:

0.0930

Hom.:

2387

Bravo

AF:

0.130

Asia WGS

AF:

0.187

AC:

651

AN:

3478

EpiCase

AF:

0.0816

EpiControl

AF:

0.0806

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 14, 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

- -

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

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

-0.79

CADD

Benign

0.057

(source)

DANN

Benign

0.61

PhyloP100

-0.053

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