rs11667110

Variant names:

• chr19-7136598-C-G
• rs11667110
• NM_000208.4:c.2683-4281G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000208.4(INSR):​c.2683-4281G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.255 in 151,746 control chromosomes in the GnomAD database, including 5,315 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.26 (5315 hom., cov: 29)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.246
• Publications: 5 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: 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.307 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.2683-4281G>C		intron_variant	Intron 13 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.2647-4281G>C		intron_variant	Intron 12 of 20		NP_001073285.1
INSR	XM_011527988.3	c.2683-4281G>C		intron_variant	Intron 13 of 21		XP_011526290.2
INSR	XM_011527989.4	c.2647-4281G>C		intron_variant	Intron 12 of 20		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.2683-4281G>C		intron_variant	Intron 13 of 21	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.2647-4281G>C		intron_variant	Intron 12 of 20	1		ENSP00000342838.4

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38711 AN: 151628 Hom.: 5316 Cov.: 29

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.294

Gnomad EAS AF: 0.262

Gnomad SAS AF: 0.253

Gnomad FIN AF: 0.263

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.310

Gnomad OTH AF: 0.271

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.255 AC: 38718 AN: 151746 Hom.: 5315 Cov.: 29 AF XY: 0.252 AC XY: 18681 AN XY: 74126

African (AFR) AF: 0.147 AC: 6096 AN: 41376

American (AMR) AF: 0.292 AC: 4435 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 1018 AN: 3466

East Asian (EAS) AF: 0.262 AC: 1352 AN: 5158

South Asian (SAS) AF: 0.254 AC: 1217 AN: 4794

European-Finnish (FIN) AF: 0.263 AC: 2764 AN: 10526

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.310 AC: 21065 AN: 67922

Other (OTH) AF: 0.271 AC: 567 AN: 2094

Alfa AF: 0.287 Hom.: 948

Bravo AF: 0.253

Asia WGS AF: 0.250 AC: 871 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.9
DANN	Benign	0.84
PhyloP100		-0.25
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11667110; hg19: chr19-7136609;