NM_000208.4:c.652+28661T>C

Variant names:

• chr19-7238684-A-G
• rs17254521
• NM_000208.4:c.652+28661T>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.652+28661T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.511 in 147,330 control chromosomes in the GnomAD database, including 20,625 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 0.51 (20625 hom., cov: 24)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.20
• Publications: 9 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=-1.05).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.694 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.652+28661T>C		intron_variant	Intron 2 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.652+28661T>C		intron_variant	Intron 2 of 20		NP_001073285.1
INSR	XM_011527988.3	c.652+28661T>C		intron_variant	Intron 2 of 21		XP_011526290.2
INSR	XM_011527989.4	c.652+28661T>C		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.652+28661T>C		intron_variant	Intron 2 of 21	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.652+28661T>C		intron_variant	Intron 2 of 20	1		ENSP00000342838.4
INSR	ENST00000598216.1	n.627+28661T>C		intron_variant	Intron 2 of 9	1

Frequencies

GnomAD3 genomes AF: 0.511 AC: 75184 AN: 147254 Hom.: 20594 Cov.: 24

Gnomad AFR AF: 0.701

Gnomad AMI AF: 0.759

Gnomad AMR AF: 0.396

Gnomad ASJ AF: 0.488

Gnomad EAS AF: 0.293

Gnomad SAS AF: 0.474

Gnomad FIN AF: 0.394

Gnomad MID AF: 0.452

Gnomad NFE AF: 0.457

Gnomad OTH AF: 0.501

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

GnomAD4 genome AF: 0.511 AC: 75243 AN: 147330 Hom.: 20625 Cov.: 24 AF XY: 0.506 AC XY: 36123 AN XY: 71354

African (AFR) AF: 0.701 AC: 27815 AN: 39664

American (AMR) AF: 0.396 AC: 5758 AN: 14558

Ashkenazi Jewish (ASJ) AF: 0.488 AC: 1687 AN: 3456

East Asian (EAS) AF: 0.293 AC: 1490 AN: 5082

South Asian (SAS) AF: 0.473 AC: 2234 AN: 4724

European-Finnish (FIN) AF: 0.394 AC: 3601 AN: 9130

Middle Eastern (MID) AF: 0.451 AC: 129 AN: 286

European-Non Finnish (NFE) AF: 0.457 AC: 30817 AN: 67492

Other (OTH) AF: 0.505 AC: 1030 AN: 2040

Alfa AF: 0.475 Hom.: 70060

Bravo AF: 0.521

Asia WGS AF: 0.439 AC: 1527 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.13
DANN	Benign	0.41
PhyloP100		-2.2
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: rs17254521; hg19: chr19-7238695;