rs2245648

Positions:

• chr19-7163219-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000208.4(INSR):​c.1862-20A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 1,594,760 control chromosomes in the GnomAD database, including 51,510 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5989 hom., cov: 30)
  • Exomes 𝑓: 0.24 (45521 hom.)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.428

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-7163219-T-C is Benign according to our data. Variant chr19-7163219-T-C is described in ClinVar as [Benign]. Clinvar id is 439839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INSR	NM_000208.4	c.1862-20A>G		intron_variant		ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.1862-20A>G		intron_variant			NP_001073285.1
INSR	XM_011527988.3	c.1862-20A>G		intron_variant			XP_011526290.2
INSR	XM_011527989.4	c.1862-20A>G		intron_variant			XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.1862-20A>G		intron_variant		1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.1862-20A>G		intron_variant		1		ENSP00000342838.4
INSR	ENST00000598216.1	n.1837-20A>G		intron_variant		1
INSR	ENST00000600492.1	c.263-20A>G		intron_variant		5		ENSP00000473170.1

Frequencies

GnomAD3 genomes AF: 0.264 AC: 40099 AN: 151696 Hom.: 5967 Cov.: 30

Gnomad AFR AF: 0.393

Gnomad AMI AF: 0.252

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.0496

Gnomad SAS AF: 0.388

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.244

Gnomad OTH AF: 0.260

GnomAD3 exomes AF: 0.224 AC: 56124 AN: 251096 Hom.: 7601 AF XY: 0.233 AC XY: 31622 AN XY: 135752

Gnomad AFR exome AF: 0.395

Gnomad AMR exome AF: 0.125

Gnomad ASJ exome AF: 0.144

Gnomad EAS exome AF: 0.0542

Gnomad SAS exome AF: 0.397

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.238

Gnomad OTH exome AF: 0.208

GnomAD4 exome AF: 0.240 AC: 346397 AN: 1442946 Hom.: 45521 Cov.: 30 AF XY: 0.245 AC XY: 176026 AN XY: 718732

Gnomad4 AFR exome AF: 0.391

Gnomad4 AMR exome AF: 0.130

Gnomad4 ASJ exome AF: 0.144

Gnomad4 EAS exome AF: 0.0442

Gnomad4 SAS exome AF: 0.389

Gnomad4 FIN exome AF: 0.119

Gnomad4 NFE exome AF: 0.244

Gnomad4 OTH exome AF: 0.233

GnomAD4 genome AF: 0.265 AC: 40172 AN: 151814 Hom.: 5989 Cov.: 30 AF XY: 0.260 AC XY: 19303 AN XY: 74178

Gnomad4 AFR AF: 0.393

Gnomad4 AMR AF: 0.177

Gnomad4 ASJ AF: 0.149

Gnomad4 EAS AF: 0.0495

Gnomad4 SAS AF: 0.387

Gnomad4 FIN AF: 0.106

Gnomad4 NFE AF: 0.244

Gnomad4 OTH AF: 0.264

Alfa AF: 0.251 Hom.: 1387

Bravo AF: 0.268

Asia WGS AF: 0.268 AC: 934 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.32
DANN	Benign	0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2245648; hg19: chr19-7163230; COSMIC: COSV57157848;