NM_000208.4:c.190T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS1

The NM_000208.4(INSR):c.190T>C(p.Leu64Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000193 in 1,614,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00083 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

INSR
NM_000208.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:4

Conservation

PhyloP100: -0.0780

Publications

0 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:

ENSG00000306258 (HGNC:):

ENSG00000306258 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 19-7267807-A-G is Benign according to our data. Variant chr19-7267807-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195041.

BP7

Synonymous conserved (PhyloP=-0.078 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000834 (127/152318) while in subpopulation AFR AF = 0.00236 (98/41578). AF 95% confidence interval is 0.00198. There are 0 homozygotes in GnomAd4. There are 58 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4 link	c.190T>C	p.Leu64Leu	synonymous_variant	Exon 2 of 22	ENST00000302850.10	NP_000199.2	P06213-1
INSR	NM_001079817.3 link	c.190T>C	p.Leu64Leu	synonymous_variant	Exon 2 of 21		NP_001073285.1	P06213-2
INSR	XM_011527988.3 link	c.190T>C	p.Leu64Leu	synonymous_variant	Exon 2 of 22		XP_011526290.2
INSR	XM_011527989.4 link	c.190T>C	p.Leu64Leu	synonymous_variant	Exon 2 of 21		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
INSR	ENST00000302850.10 link	c.190T>C	p.Leu64Leu	synonymous_variant	Exon 2 of 22	1	NM_000208.4	ENSP00000303830.4	P06213-1
INSR	ENST00000341500.9 link	c.190T>C	p.Leu64Leu	synonymous_variant	Exon 2 of 21	1		ENSP00000342838.4	P06213-2
INSR	ENST00000598216.1 link	n.165T>C		non_coding_transcript_exon_variant	Exon 2 of 10	1
ENSG00000306258	ENST00000816520.1 link	n.439A>G		non_coding_transcript_exon_variant	Exon 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.000834

AC:

127

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00236

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000251

AC:

AN:

251380

AF XY:

0.000221

show subpopulations

Gnomad AFR exome

AF:

0.00283

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000126

AC:

184

AN:

1461858

Hom.:

Cov.:

AF XY:

0.000136

AC XY:

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00311

AC:

104

AN:

33480

American (AMR)

AF:

0.000470

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000162

AC:

AN:

1111982

Other (OTH)

AF:

0.000397

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000834

AC:

127

AN:

152318

Hom.:

Cov.:

AF XY:

0.000779

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00236

AC:

AN:

41578

American (AMR)

AF:

0.00150

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68026

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000637

Hom.:

Bravo

AF:

0.00123

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Sep 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 28, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Insulin-resistant diabetes mellitus AND acanthosis nigricans

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Rabson-Mendenhall syndrome

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Leprechaunism syndrome

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Mar 09, 2016

Genetic Services Laboratory, University of Chicago

Significance:Likely 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 rs144836032 with early onset diabetes mellitus is yet to be ascertained. -

INSR-related disorder

Benign:1

Feb 18, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

1.3

(source)

DANN

Benign

0.61

PhyloP100

-0.078

Mutation Taster

=100/0

polymorphism

(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