rs1799816

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr19-7125507-C-T
• chr19-7125507-C-G

Variant summary

Our verdict is Benign. The variant received -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:13
• Conservation: PhyloP100: 2.61
• Publications: 42 publications found

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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• Donohue syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• hyperinsulinism due to INSR deficiency

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Rabson-Mendenhall syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 Donohue syndrome, insulin-resistance syndrome type A, Rabson-Mendenhall syndrome, hyperinsulinism due to INSR deficiency.
• 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 VariationId is 14707.
• 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000208.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	NM_000208.4	MANE Select	c.3034G>A	p.Val1012Met	missense	Exon 17 of 22	NP_000199.2	P06213-1
	INSR	NM_001079817.3		c.2998G>A	p.Val1000Met	missense	Exon 16 of 21	NP_001073285.1	P06213-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	ENST00000302850.10	TSL:1 MANE Select	c.3034G>A	p.Val1012Met	missense	Exon 17 of 22	ENSP00000303830.4	P06213-1
	INSR	ENST00000341500.9	TSL:1	c.2998G>A	p.Val1000Met	missense	Exon 16 of 21	ENSP00000342838.4	P06213-2
	INSR	ENST00000904791.1		c.3031G>A	p.Val1011Met	missense	Exon 17 of 22	ENSP00000574850.1

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

GnomAD2 exomes AF: 0.00841 AC: 2113 AN: 251110 AF XY: 0.00964

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 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

African (AFR) AF: 0.00116 AC: 39 AN: 33480

American (AMR) AF: 0.00217 AC: 97 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 422 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0231 AC: 1991 AN: 86258

European-Finnish (FIN) AF: 0.00686 AC: 365 AN: 53172

Middle Eastern (MID) AF: 0.0165 AC: 95 AN: 5768

European-Non Finnish (NFE) AF: 0.00704 AC: 7827 AN: 1111998

Other (OTH) AF: 0.00836 AC: 505 AN: 60396

GnomAD4 genome AF: 0.00540 AC: 823 AN: 152268 Hom.: 2 Cov.: 31 AF XY: 0.00539 AC XY: 401 AN XY: 74440

African (AFR) AF: 0.00130 AC: 54 AN: 41564

American (AMR) AF: 0.00471 AC: 72 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 51 AN: 3462

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.0178 AC: 86 AN: 4828

European-Finnish (FIN) AF: 0.00594 AC: 63 AN: 10610

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00707 AC: 481 AN: 68022

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00713 Hom.: 95

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	2	not specified (3)
-	-	2	Insulin-resistant diabetes mellitus AND acanthosis nigricans (2)
-	-	2	Rabson-Mendenhall syndrome (2)
-	-	1	Bailey-Bloch congenital myopathy (1)
-	-	1	Leprechaunism syndrome (1)
-	-	1	Monogenic diabetes (1)
-	1	-	Type 2 diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	0.64	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		2.6
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.63
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	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
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

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