19-7125507-C-T

Variant names:

• chr19-7125507-C-T
• rs1799816
• NM_000208.4:c.3034G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:12
• Conservation: PhyloP100: 2.61

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP2: Missense variant in the INSR gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 3.8314 (above the threshold of 3.09). Trascript score misZ: 5.4593 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.3034G>A	p.Val1012Met	missense_variant	Exon 17 of 22	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.2998G>A	p.Val1000Met	missense_variant	Exon 16 of 21		NP_001073285.1
INSR	XM_011527988.3	c.3031G>A	p.Val1011Met	missense_variant	Exon 17 of 22		XP_011526290.2
INSR	XM_011527989.4	c.2995G>A	p.Val999Met	missense_variant	Exon 16 of 21		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.3034G>A	p.Val1012Met	missense_variant	Exon 17 of 22	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.2998G>A	p.Val1000Met	missense_variant	Exon 16 of 21	1		ENSP00000342838.4
INSR	ENST00000593970.1	n.-121G>A		upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00542 AC: 824 AN: 152150 Hom.: 2 Cov.: 31

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.: 18 AF XY: 0.00964 AC XY: 1309 AN XY: 135724

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.: 81 Cov.: 33 AF XY: 0.00848 AC XY: 6166 AN XY: 727122

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.: 2 Cov.: 31 AF XY: 0.00539 AC XY: 401 AN XY: 74440

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.: 9

Bravo AF: 0.00499

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00860 AC: 74

ExAC AF: 0.00898 AC: 1090

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.00714

EpiControl AF: 0.00699

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

INSR: PP2, BS1, BS2 -

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 23, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1 Benign:2

Jan 28, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Insulin-resistant diabetes mellitus AND acanthosis nigricans Benign:2

Mar 06, 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. -

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Type 2 diabetes mellitus Uncertain:1

Mar 01, 1999

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Rabson-Mendenhall syndrome Benign:1

Mar 06, 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. -

Monogenic diabetes Benign:1

Jan 08, 2018

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

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

-

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

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

Mar 06, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	.;D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.92	D;D
MetaRNN	Benign	0.010	T;T
MetaSVM	Uncertain	0.64	D
MutationAssessor	Uncertain	2.9	.;M
PrimateAI	Uncertain	0.77	T
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	T
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

Other links and lift over

dbSNP: rs1799816; hg19: chr19-7125518; COSMIC: COSV100252426; COSMIC: COSV100252426;