19-7145363-C-T

Variant names:

• chr19-7145363-C-T
• rs8103483
• NM_000208.4:c.2268-2273G>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.2268-2273G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.4 in 151,716 control chromosomes in the GnomAD database, including 13,423 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 0.40 (13423 hom., cov: 32)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.819
• Publications: 12 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=-0.96).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.2268-2273G>A		intron_variant	Intron 11 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.2232-2273G>A		intron_variant	Intron 10 of 20		NP_001073285.1
INSR	XM_011527988.3	c.2268-2273G>A		intron_variant	Intron 11 of 21		XP_011526290.2
INSR	XM_011527989.4	c.2232-2273G>A		intron_variant	Intron 10 of 20		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.2268-2273G>A		intron_variant	Intron 11 of 21	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.2232-2273G>A		intron_variant	Intron 10 of 20	1		ENSP00000342838.4

Frequencies

GnomAD3 genomes AF: 0.401 AC: 60744 AN: 151596 Hom.: 13423 Cov.: 32

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.622

Gnomad AMR AF: 0.355

Gnomad ASJ AF: 0.415

Gnomad EAS AF: 0.0878

Gnomad SAS AF: 0.465

Gnomad FIN AF: 0.501

Gnomad MID AF: 0.490

Gnomad NFE AF: 0.506

Gnomad OTH AF: 0.406

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

GnomAD4 genome AF: 0.400 AC: 60755 AN: 151716 Hom.: 13423 Cov.: 32 AF XY: 0.397 AC XY: 29454 AN XY: 74116

African (AFR) AF: 0.243 AC: 10055 AN: 41350

American (AMR) AF: 0.355 AC: 5402 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.415 AC: 1438 AN: 3464

East Asian (EAS) AF: 0.0874 AC: 452 AN: 5172

South Asian (SAS) AF: 0.466 AC: 2248 AN: 4822

European-Finnish (FIN) AF: 0.501 AC: 5255 AN: 10482

Middle Eastern (MID) AF: 0.497 AC: 145 AN: 292

European-Non Finnish (NFE) AF: 0.506 AC: 34337 AN: 67892

Other (OTH) AF: 0.407 AC: 856 AN: 2104

Alfa AF: 0.472 Hom.: 30844

Bravo AF: 0.381

Asia WGS AF: 0.319 AC: 1109 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.039
DANN	Benign	0.83
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: rs8103483; hg19: chr19-7145374;