chr19-7251090-G-A

Variant names:

• chr19-7251090-G-A
• rs11671297
• NM_000208.4:c.652+16255C>T

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+16255C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.564 in 151,674 control chromosomes in the GnomAD database, including 24,358 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 0.56 (24358 hom., cov: 30)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.33
• Publications: 10 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=-1.0).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.605 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	NM_000208.4	MANE Select	c.652+16255C>T		intron	N/A	NP_000199.2
	INSR	NM_001079817.3		c.652+16255C>T		intron	N/A	NP_001073285.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	ENST00000302850.10	TSL:1 MANE Select	c.652+16255C>T		intron	N/A	ENSP00000303830.4
	INSR	ENST00000341500.9	TSL:1	c.652+16255C>T		intron	N/A	ENSP00000342838.4
	INSR	ENST00000598216.1	TSL:1	n.627+16255C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.564 AC: 85425 AN: 151554 Hom.: 24327 Cov.: 30

Gnomad AFR AF: 0.540

Gnomad AMI AF: 0.725

Gnomad AMR AF: 0.614

Gnomad ASJ AF: 0.560

Gnomad EAS AF: 0.547

Gnomad SAS AF: 0.481

Gnomad FIN AF: 0.583

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.571

Gnomad OTH AF: 0.521

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

GnomAD4 genome AF: 0.564 AC: 85495 AN: 151674 Hom.: 24358 Cov.: 30 AF XY: 0.563 AC XY: 41724 AN XY: 74130

African (AFR) AF: 0.539 AC: 22230 AN: 41210

American (AMR) AF: 0.615 AC: 9377 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.560 AC: 1945 AN: 3472

East Asian (EAS) AF: 0.547 AC: 2819 AN: 5158

South Asian (SAS) AF: 0.482 AC: 2314 AN: 4802

European-Finnish (FIN) AF: 0.583 AC: 6152 AN: 10550

Middle Eastern (MID) AF: 0.510 AC: 150 AN: 294

European-Non Finnish (NFE) AF: 0.571 AC: 38758 AN: 67924

Other (OTH) AF: 0.516 AC: 1089 AN: 2110

Alfa AF: 0.568 Hom.: 23321

Bravo AF: 0.567

Asia WGS AF: 0.517 AC: 1798 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.3
DANN	Benign	0.38
PhyloP100		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs11671297; hg19: chr19-7251101;