rs17254521

Positions:

• chr19-7238684-A-G

Variant summary

Our verdict is Benign. Variant got -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

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=-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/exons	MANE	UniProt
INSR	NM_000208.4	c.652+28661T>C		intron_variant		ENST00000302850.10
INSR	NM_001079817.3	c.652+28661T>C		intron_variant
INSR	XM_011527988.3	c.652+28661T>C		intron_variant
INSR	XM_011527989.4	c.652+28661T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INSR	ENST00000302850.10	c.652+28661T>C		intron_variant		1	NM_000208.4	A2
INSR	ENST00000341500.9	c.652+28661T>C		intron_variant		1		P3
INSR	ENST00000598216.1	n.627+28661T>C		intron_variant, non_coding_transcript_variant		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

Gnomad4 AFR AF: 0.701

Gnomad4 AMR AF: 0.396

Gnomad4 ASJ AF: 0.488

Gnomad4 EAS AF: 0.293

Gnomad4 SAS AF: 0.473

Gnomad4 FIN AF: 0.394

Gnomad4 NFE AF: 0.457

Gnomad4 OTH AF: 0.505

Alfa AF: 0.470 Hom.: 30677

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

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: rs17254521; hg19: chr19-7238695;