rs12460755

Variant names:

• chr19-7231668-G-A
• rs12460755
• NM_000208.4:c.652+35677C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-7231668-G-A
• chr19-7231668-G-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+35677C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 151,880 control chromosomes in the GnomAD database, including 5,027 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 0.23 (5027 hom., cov: 30)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0390
• Publications: 11 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.652+35677C>T		intron_variant	Intron 2 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.652+35677C>T		intron_variant	Intron 2 of 20		NP_001073285.1
INSR	XM_011527988.3	c.652+35677C>T		intron_variant	Intron 2 of 21		XP_011526290.2
INSR	XM_011527989.4	c.652+35677C>T		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+35677C>T		intron_variant	Intron 2 of 21	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.652+35677C>T		intron_variant	Intron 2 of 20	1		ENSP00000342838.4
INSR	ENST00000598216.1	n.627+35677C>T		intron_variant	Intron 2 of 9	1

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34654 AN: 151760 Hom.: 5030 Cov.: 30

Gnomad AFR AF: 0.0586

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.313

Gnomad EAS AF: 0.0962

Gnomad SAS AF: 0.286

Gnomad FIN AF: 0.350

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.245

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

GnomAD4 genome AF: 0.228 AC: 34640 AN: 151880 Hom.: 5027 Cov.: 30 AF XY: 0.230 AC XY: 17082 AN XY: 74186

African (AFR) AF: 0.0584 AC: 2422 AN: 41466

American (AMR) AF: 0.229 AC: 3494 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 1087 AN: 3468

East Asian (EAS) AF: 0.0957 AC: 495 AN: 5174

South Asian (SAS) AF: 0.286 AC: 1376 AN: 4808

European-Finnish (FIN) AF: 0.350 AC: 3672 AN: 10498

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.315 AC: 21400 AN: 67930

Other (OTH) AF: 0.243 AC: 511 AN: 2106

Alfa AF: 0.267 Hom.: 3106

Bravo AF: 0.210

Asia WGS AF: 0.203 AC: 708 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.1
DANN	Benign	0.63
PhyloP100		0.039
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.97
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: rs12460755; hg19: chr19-7231679;