rs2245649

Variant names:

• chr19-7163203-T-C
• rs2245649
• NM_000208.4:c.1862-4A>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.1862-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0909 in 1,602,380 control chromosomes in the GnomAD database, including 9,322 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1700 hom., cov: 30)
  • Exomes 𝑓: 0.087 (7622 hom.)
• Consequence: INSR NM_000208.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001008
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.40
• Publications: 19 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: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P
• Donohue syndrome

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

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

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 19-7163203-T-C is Benign according to our data. Variant chr19-7163203-T-C is described in ClinVar as Benign. ClinVar VariationId is 330469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.241 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

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

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19104 AN: 151808 Hom.: 1693 Cov.: 30

Gnomad AFR AF: 0.245

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.0829

Gnomad ASJ AF: 0.0461

Gnomad EAS AF: 0.0284

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.0387

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0796

Gnomad OTH AF: 0.118

GnomAD2 exomes AF: 0.0983 AC: 24702 AN: 251252 AF XY: 0.104

Gnomad AFR exome AF: 0.243

Gnomad AMR exome AF: 0.0601

Gnomad ASJ exome AF: 0.0490

Gnomad EAS exome AF: 0.0259

Gnomad FIN exome AF: 0.0449

Gnomad NFE exome AF: 0.0774

Gnomad OTH exome AF: 0.0917

GnomAD4 exome AF: 0.0873 AC: 126575 AN: 1450454 Hom.: 7622 Cov.: 31 AF XY: 0.0915 AC XY: 66083 AN XY: 722058

African (AFR) AF: 0.242 AC: 7956 AN: 32884

American (AMR) AF: 0.0633 AC: 2831 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0474 AC: 1236 AN: 26080

East Asian (EAS) AF: 0.0302 AC: 1198 AN: 39652

South Asian (SAS) AF: 0.233 AC: 19944 AN: 85758

European-Finnish (FIN) AF: 0.0453 AC: 2420 AN: 53386

Middle Eastern (MID) AF: 0.112 AC: 637 AN: 5700

European-Non Finnish (NFE) AF: 0.0768 AC: 84687 AN: 1102320

Other (OTH) AF: 0.0945 AC: 5666 AN: 59972

GnomAD4 genome AF: 0.126 AC: 19148 AN: 151926 Hom.: 1700 Cov.: 30 AF XY: 0.125 AC XY: 9314 AN XY: 74256

African (AFR) AF: 0.245 AC: 10163 AN: 41414

American (AMR) AF: 0.0828 AC: 1262 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.0461 AC: 160 AN: 3472

East Asian (EAS) AF: 0.0282 AC: 146 AN: 5170

South Asian (SAS) AF: 0.244 AC: 1169 AN: 4794

European-Finnish (FIN) AF: 0.0387 AC: 410 AN: 10584

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0796 AC: 5410 AN: 67950

Other (OTH) AF: 0.123 AC: 258 AN: 2100

Alfa AF: 0.101 Hom.: 766

Bravo AF: 0.130

Asia WGS AF: 0.187 AC: 651 AN: 3478

EpiCase AF: 0.0816

EpiControl AF: 0.0806

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Insulin-resistant diabetes mellitus AND acanthosis nigricans (1)
-	-	1	Leprechaunism syndrome (1)
-	-	1	Rabson-Mendenhall syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.64
DANN	Benign	0.77
PhyloP100		-3.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00010
dbscSNV1_RF	Benign	0.0
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: rs2245649; hg19: chr19-7163214; COSMIC: COSV57159596;