19-7196554-C-T

Variant names:

• chr19-7196554-C-T
• rs2115386
• NM_000208.4:c.653-11917G>A

Variant summary

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

The NM_000208.4(INSR):​c.653-11917G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.483 in 151,970 control chromosomes in the GnomAD database, including 17,697 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 0.48 (17697 hom., cov: 32)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.824
• Publications: 27 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.518 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.653-11917G>A		intron_variant	Intron 2 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.653-11917G>A		intron_variant	Intron 2 of 20		NP_001073285.1
INSR	XM_011527988.3	c.653-11917G>A		intron_variant	Intron 2 of 21		XP_011526290.2
INSR	XM_011527989.4	c.653-11917G>A		intron_variant	Intron 2 of 20		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.653-11917G>A		intron_variant	Intron 2 of 21	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.653-11917G>A		intron_variant	Intron 2 of 20	1		ENSP00000342838.4
INSR	ENST00000598216.1	n.628-11917G>A		intron_variant	Intron 2 of 9	1

Frequencies

GnomAD3 genomes AF: 0.483 AC: 73296 AN: 151852 Hom.: 17686 Cov.: 32

Gnomad AFR AF: 0.447

Gnomad AMI AF: 0.674

Gnomad AMR AF: 0.486

Gnomad ASJ AF: 0.443

Gnomad EAS AF: 0.535

Gnomad SAS AF: 0.469

Gnomad FIN AF: 0.567

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.487

Gnomad OTH AF: 0.460

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

GnomAD4 genome AF: 0.483 AC: 73341 AN: 151970 Hom.: 17697 Cov.: 32 AF XY: 0.485 AC XY: 36029 AN XY: 74284

African (AFR) AF: 0.447 AC: 18533 AN: 41444

American (AMR) AF: 0.486 AC: 7412 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.443 AC: 1536 AN: 3468

East Asian (EAS) AF: 0.534 AC: 2769 AN: 5182

South Asian (SAS) AF: 0.467 AC: 2252 AN: 4822

European-Finnish (FIN) AF: 0.567 AC: 5981 AN: 10540

Middle Eastern (MID) AF: 0.497 AC: 146 AN: 294

European-Non Finnish (NFE) AF: 0.487 AC: 33128 AN: 67956

Other (OTH) AF: 0.462 AC: 971 AN: 2104

Alfa AF: 0.481 Hom.: 44029

Bravo AF: 0.478

Asia WGS AF: 0.496 AC: 1724 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.21
DANN	Benign	0.74
PhyloP100		-0.82
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: rs2115386; hg19: chr19-7196565;