rs2059807

chr19-7166098-A-Gchr19-7166098-A-T

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.1861+56T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.6 in 1,606,108 control chromosomes in the GnomAD database, including 293,867 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.63 (30530 hom., cov: 29)
  • Exomes 𝑓: 0.60 (263337 hom.)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0280

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=-0.91).
• BP6: Variant 19-7166098-A-G is Benign according to our data. Variant chr19-7166098-A-G is described in ClinVar as [Benign]. Clinvar id is 1253612.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.759 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INSR	NM_000208.4	c.1861+56T>C		intron_variant		ENST00000302850.10
INSR	NM_001079817.3	c.1861+56T>C		intron_variant
INSR	XM_011527988.3	c.1861+56T>C		intron_variant
INSR	XM_011527989.4	c.1861+56T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INSR	ENST00000302850.10	c.1861+56T>C		intron_variant		1	NM_000208.4	A2
INSR	ENST00000341500.9	c.1861+56T>C		intron_variant		1		P3
INSR	ENST00000598216.1	n.1836+56T>C		intron_variant, non_coding_transcript_variant		1
INSR	ENST00000600492.1	c.262+56T>C		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.628 AC: 94905 AN: 151206 Hom.: 30470 Cov.: 29

Gnomad AFR AF: 0.766

Gnomad AMI AF: 0.695

Gnomad AMR AF: 0.512

Gnomad ASJ AF: 0.639

Gnomad EAS AF: 0.341

Gnomad SAS AF: 0.675

Gnomad FIN AF: 0.533

Gnomad MID AF: 0.661

Gnomad NFE AF: 0.600

Gnomad OTH AF: 0.662

GnomAD4 exome AF: 0.597 AC: 868927 AN: 1454784 Hom.: 263337 AF XY: 0.600 AC XY: 434742 AN XY: 724110

Gnomad4 AFR exome AF: 0.771

Gnomad4 AMR exome AF: 0.460

Gnomad4 ASJ exome AF: 0.641

Gnomad4 EAS exome AF: 0.301

Gnomad4 SAS exome AF: 0.684

Gnomad4 FIN exome AF: 0.527

Gnomad4 NFE exome AF: 0.603

Gnomad4 OTH exome AF: 0.602

GnomAD4 genome AF: 0.628 AC: 95010 AN: 151324 Hom.: 30530 Cov.: 29 AF XY: 0.624 AC XY: 46089 AN XY: 73890

Gnomad4 AFR AF: 0.767

Gnomad4 AMR AF: 0.512

Gnomad4 ASJ AF: 0.639

Gnomad4 EAS AF: 0.340

Gnomad4 SAS AF: 0.675

Gnomad4 FIN AF: 0.533

Gnomad4 NFE AF: 0.600

Gnomad4 OTH AF: 0.665

Alfa AF: 0.609 Hom.: 39773

Bravo AF: 0.628

Asia WGS AF: 0.593 AC: 2064 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

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	4.0
Dann	Benign	0.37

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: rs2059807; hg19: chr19-7166109; COSMIC: COSV57161688;