rs12460755

Positions:

• chr19-7231668-G-A
• chr19-7231668-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000302850.10(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 ENST00000302850.10 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0390

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
INSR	NM_000208.4	c.652+35677C>T		intron_variant		ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.652+35677C>T		intron_variant			NP_001073285.1
INSR	XM_011527988.3	c.652+35677C>T		intron_variant			XP_011526290.2
INSR	XM_011527989.4	c.652+35677C>T		intron_variant			XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.652+35677C>T		intron_variant		1	NM_000208.4	ENSP00000303830	A2
INSR	ENST00000341500.9	c.652+35677C>T		intron_variant		1		ENSP00000342838	P3
INSR	ENST00000598216.1	n.627+35677C>T		intron_variant, non_coding_transcript_variant		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

Gnomad4 AFR AF: 0.0584

Gnomad4 AMR AF: 0.229

Gnomad4 ASJ AF: 0.313

Gnomad4 EAS AF: 0.0957

Gnomad4 SAS AF: 0.286

Gnomad4 FIN AF: 0.350

Gnomad4 NFE AF: 0.315

Gnomad4 OTH AF: 0.243

Alfa AF: 0.264 Hom.: 2739

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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.97

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

Publications

LitVar

Other links and lift over

dbSNP: rs12460755; hg19: chr19-7231679;