rs2245648

Variant names:

• chr19-7163219-T-C
• rs2245648
• NM_000208.4:c.1862-20A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• insulin-resistance syndrome type A

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• Donohue syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• hyperinsulinism due to INSR deficiency

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Rabson-Mendenhall syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000208.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	NM_000208.4	MANE Select	c.1862-20A>G		intron	N/A	NP_000199.2	P06213-1
	INSR	NM_001079817.3		c.1862-20A>G		intron	N/A	NP_001073285.1	P06213-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	ENST00000302850.10	TSL:1 MANE Select	c.1862-20A>G		intron	N/A	ENSP00000303830.4	P06213-1
	INSR	ENST00000341500.9	TSL:1	c.1862-20A>G		intron	N/A	ENSP00000342838.4	P06213-2
	INSR	ENST00000598216.1	TSL:1	n.1837-20A>G		intron	N/A

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

GnomAD2 exomes AF: 0.224 AC: 56124 AN: 251096 AF XY: 0.233

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 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

African (AFR) AF: 0.391 AC: 12728 AN: 32552

American (AMR) AF: 0.130 AC: 5805 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 3760 AN: 26052

East Asian (EAS) AF: 0.0442 AC: 1751 AN: 39632

South Asian (SAS) AF: 0.389 AC: 33221 AN: 85448

European-Finnish (FIN) AF: 0.119 AC: 6340 AN: 53344

Middle Eastern (MID) AF: 0.247 AC: 1401 AN: 5678

European-Non Finnish (NFE) AF: 0.244 AC: 267478 AN: 1095820

Other (OTH) AF: 0.233 AC: 13913 AN: 59718

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

African (AFR) AF: 0.393 AC: 16276 AN: 41370

American (AMR) AF: 0.177 AC: 2684 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 518 AN: 3472

East Asian (EAS) AF: 0.0495 AC: 256 AN: 5172

South Asian (SAS) AF: 0.387 AC: 1860 AN: 4802

European-Finnish (FIN) AF: 0.106 AC: 1115 AN: 10562

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.244 AC: 16604 AN: 67930

Other (OTH) AF: 0.264 AC: 555 AN: 2104

Alfa AF: 0.250 Hom.: 2127

Bravo AF: 0.268

Asia WGS AF: 0.268 AC: 934 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.32
DANN	Benign	0.46
PhyloP100		-0.43
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2245648; hg19: chr19-7163230; COSMIC: COSV57157848;