rs1799816

Positions:

chr19-7125507-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_000208.4(INSR):c.3034G>A(p.Val1012Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00754 in 1,613,900 control chromosomes in the GnomAD database, including 83 homozygotes. 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 0.0054 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0078 ( 81 hom. )

Consequence

INSR
NM_000208.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:12

Conservation

PhyloP100: 2.61

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), INSR. . Gene score misZ 3.8314 (greater than the threshold 3.09). Trascript score misZ 5.4593 (greater than threshold 3.09). GenCC has associacion of gene with insulin-resistance syndrome type A, hyperinsulinism due to INSR deficiency, Rabson-Mendenhall syndrome, Donohue syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.010013849).

BP6

Variant 19-7125507-C-T is Benign according to our data. Variant chr19-7125507-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14707.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=7, Uncertain_significance=1}. Variant chr19-7125507-C-T is described in Lovd as [Likely_benign]. Variant chr19-7125507-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0054 (823/152268) while in subpopulation SAS AF= 0.0178 (86/4828). AF 95% confidence interval is 0.0148. There are 2 homozygotes in gnomad4. There are 401 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
INSR	NM_000208.4 linkuse as main transcript	c.3034G>A	p.Val1012Met	missense_variant	17/22	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3 linkuse as main transcript	c.2998G>A	p.Val1000Met	missense_variant	16/21		NP_001073285.1
INSR	XM_011527988.3 linkuse as main transcript	c.3031G>A	p.Val1011Met	missense_variant	17/22		XP_011526290.2
INSR	XM_011527989.4 linkuse as main transcript	c.2995G>A	p.Val999Met	missense_variant	16/21		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10 linkuse as main transcript	c.3034G>A	p.Val1012Met	missense_variant	17/22	1	NM_000208.4	ENSP00000303830	A2	P06213-1
INSR	ENST00000341500.9 linkuse as main transcript	c.2998G>A	p.Val1000Met	missense_variant	16/21	1		ENSP00000342838	P3	P06213-2

Frequencies

GnomAD3 genomes

AF:

0.00542

AC:

824

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00472

Gnomad ASJ

AF:

0.0147

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0180

Gnomad FIN

AF:

0.00594

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00707

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00841

AC:

2113

AN:

251110

Hom.:

AF XY:

0.00964

AC XY:

1309

AN XY:

135724

show subpopulations

Gnomad AFR exome

AF:

0.00166

Gnomad AMR exome

AF:

0.00217

Gnomad ASJ exome

AF:

0.0178

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0224

Gnomad FIN exome

AF:

0.00716

Gnomad NFE exome

AF:

0.00839

Gnomad OTH exome

AF:

0.00603

GnomAD4 exome

AF:

0.00776

AC:

11343

AN:

1461632

Hom.:

Cov.:

AF XY:

0.00848

AC XY:

6166

AN XY:

727122

show subpopulations

Gnomad4 AFR exome

AF:

0.00116

Gnomad4 AMR exome

AF:

0.00217

Gnomad4 ASJ exome

AF:

0.0161

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0231

Gnomad4 FIN exome

AF:

0.00686

Gnomad4 NFE exome

AF:

0.00704

Gnomad4 OTH exome

AF:

0.00836

GnomAD4 genome

AF:

0.00540

AC:

823

AN:

152268

Hom.:

Cov.:

AF XY:

0.00539

AC XY:

401

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.00130

Gnomad4 AMR

AF:

0.00471

Gnomad4 ASJ

AF:

0.0147

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0178

Gnomad4 FIN

AF:

0.00594

Gnomad4 NFE

AF:

0.00707

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00756

Hom.:

Bravo

AF:

0.00499

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00860

AC:

ExAC

AF:

0.00898

AC:

1090

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.00714

EpiControl

AF:

0.00699

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 23, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	INSR: PP2, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

not specified

Uncertain:1Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 01, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 28, 2015	- -

Insulin-resistant diabetes mellitus AND acanthosis nigricans

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Type 2 diabetes mellitus

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Mar 01, 1999

- -

Rabson-Mendenhall syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

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. -

Monogenic diabetes

Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jan 08, 2018

ACMG criteria: PP3 (8 predictors), BS2 (107 controls in T2DM and 92 cases in type2diabetesgenetics.org), BS1 (1.53% in South Asian population in 1000g and 2.25% in ExAC South Asian pop), BP6 (Benign from Emory, but conflicting data (VUS from Chicago, LB from Illumina and Children's Mercy)=benign -

Bailey-Bloch congenital myopathy

Benign:1

Likely benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

The heterozygous p.Val1012Met variant in INSR has been identified in an individual with non-insulin-dependent diabetes mellitus and an unaffected individual (PMID: 2040394). This variant has also been identified in >2% of South Asian chromosomes and 11 homozygotes by ExAC (http://gnomad.broadinstitute.org/). Please note that individuals in ExAC may have type II diabetes. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for non-insulin-dependent diabetes mellitus NIDDM. -

Leprechaunism syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.094

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.66

.;D

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.92

D;D

MetaRNN

Benign

0.010

T;T

MetaSVM

Uncertain

0.64

MutationAssessor

Uncertain

2.9

.;M

MutationTaster

Benign

0.93

A;A

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-2.4

N;N

REVEL

Uncertain

0.63

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.016

D;D

Polyphen

1.0

D;D

Vest4

0.44

MVP

0.95

MPC

1.4

ClinPred

0.053

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.26

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over