rs2059807

Variant names:

• chr19-7166098-A-G
• rs2059807
• NM_000208.4:c.1861+56T>C

Your query was ambiguous. Multiple possible variants found:

• chr19-7166098-A-G
• chr19-7166098-A-C
• chr19-7166098-A-T

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.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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0280
• Publications: 67 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=-0.91).
• BP6: Variant 19-7166098-A-G is Benign according to our data. Variant chr19-7166098-A-G is described in ClinVar as Benign. ClinVar VariationId is 1253612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.759 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.1861+56T>C		intron	N/A	NP_000199.2	P06213-1
	INSR	NM_001079817.3		c.1861+56T>C		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.1861+56T>C		intron	N/A	ENSP00000303830.4	P06213-1
	INSR	ENST00000341500.9	TSL:1	c.1861+56T>C		intron	N/A	ENSP00000342838.4	P06213-2
	INSR	ENST00000598216.1	TSL:1	n.1836+56T>C		intron	N/A

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

African (AFR) AF: 0.771 AC: 25752 AN: 33380

American (AMR) AF: 0.460 AC: 20553 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.641 AC: 16722 AN: 26090

East Asian (EAS) AF: 0.301 AC: 11940 AN: 39606

South Asian (SAS) AF: 0.684 AC: 58659 AN: 85700

European-Finnish (FIN) AF: 0.527 AC: 28110 AN: 53314

Middle Eastern (MID) AF: 0.669 AC: 3844 AN: 5748

European-Non Finnish (NFE) AF: 0.603 AC: 667173 AN: 1106122

Other (OTH) AF: 0.602 AC: 36174 AN: 60122

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

African (AFR) AF: 0.767 AC: 31531 AN: 41136

American (AMR) AF: 0.512 AC: 7756 AN: 15158

Ashkenazi Jewish (ASJ) AF: 0.639 AC: 2217 AN: 3472

East Asian (EAS) AF: 0.340 AC: 1751 AN: 5146

South Asian (SAS) AF: 0.675 AC: 3242 AN: 4800

European-Finnish (FIN) AF: 0.533 AC: 5536 AN: 10394

Middle Eastern (MID) AF: 0.660 AC: 194 AN: 294

European-Non Finnish (NFE) AF: 0.600 AC: 40750 AN: 67908

Other (OTH) AF: 0.665 AC: 1399 AN: 2104

Alfa AF: 0.611 Hom.: 92754

Bravo AF: 0.628

Asia WGS AF: 0.593 AC: 2064 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.0
DANN	Benign	0.37
PhyloP100		0.028
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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