rs2252673

Positions:

• chr19-7150407-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000208.4(INSR):​c.2267+90G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.784 in 1,251,622 control chromosomes in the GnomAD database, including 392,313 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.74 (42976 hom., cov: 34)
  • Exomes 𝑓: 0.79 (349337 hom.)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.462

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-7150407-C-G is Benign according to our data. Variant chr19-7150407-C-G is described in ClinVar as [Benign]. Clinvar id is 1246658.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.818 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INSR	NM_000208.4	c.2267+90G>C		intron_variant		ENST00000302850.10
INSR	NM_001079817.3	c.2231+2319G>C		intron_variant
INSR	XM_011527988.3	c.2267+90G>C		intron_variant
INSR	XM_011527989.4	c.2231+2319G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INSR	ENST00000302850.10	c.2267+90G>C		intron_variant		1	NM_000208.4	A2
INSR	ENST00000341500.9	c.2231+2319G>C		intron_variant		1		P3

Frequencies

GnomAD3 genomes AF: 0.744 AC: 113081 AN: 152056 Hom.: 42953 Cov.: 34

Gnomad AFR AF: 0.683

Gnomad AMI AF: 0.746

Gnomad AMR AF: 0.658

Gnomad ASJ AF: 0.734

Gnomad EAS AF: 0.345

Gnomad SAS AF: 0.763

Gnomad FIN AF: 0.782

Gnomad MID AF: 0.774

Gnomad NFE AF: 0.823

Gnomad OTH AF: 0.744

GnomAD4 exome AF: 0.789 AC: 867898 AN: 1099446 Hom.: 349337 AF XY: 0.791 AC XY: 443326 AN XY: 560728

Gnomad4 AFR exome AF: 0.684

Gnomad4 AMR exome AF: 0.596

Gnomad4 ASJ exome AF: 0.726

Gnomad4 EAS exome AF: 0.292

Gnomad4 SAS exome AF: 0.773

Gnomad4 FIN exome AF: 0.786

Gnomad4 NFE exome AF: 0.832

Gnomad4 OTH exome AF: 0.762

GnomAD4 genome AF: 0.744 AC: 113143 AN: 152176 Hom.: 42976 Cov.: 34 AF XY: 0.736 AC XY: 54743 AN XY: 74372

Gnomad4 AFR AF: 0.683

Gnomad4 AMR AF: 0.657

Gnomad4 ASJ AF: 0.734

Gnomad4 EAS AF: 0.344

Gnomad4 SAS AF: 0.764

Gnomad4 FIN AF: 0.782

Gnomad4 NFE AF: 0.823

Gnomad4 OTH AF: 0.746

Alfa AF: 0.778 Hom.: 5758

Bravo AF: 0.728

Asia WGS AF: 0.609 AC: 2121 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	13
DANN	Benign	0.69

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: rs2252673; hg19: chr19-7150418; COSMIC: COSV57173311; COSMIC: COSV57173311;