rs2860175

Variant names:

• chr19-7132070-C-T
• rs2860175
• NM_000208.4:c.2842+88G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-7132070-C-T
• chr19-7132070-C-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.2842+88G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 1,524,078 control chromosomes in the GnomAD database, including 12,119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2251 hom., cov: 31)
  • Exomes 𝑓: 0.11 (9868 hom.)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.40
• Publications: 9 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=-0.92).
• BP6: Variant 19-7132070-C-T is Benign according to our data. Variant chr19-7132070-C-T is described in ClinVar as Benign. ClinVar VariationId is 1282339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.258 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.2842+88G>A		intron	N/A	NP_000199.2	P06213-1
	INSR	NM_001079817.3		c.2806+88G>A		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.2842+88G>A		intron	N/A	ENSP00000303830.4	P06213-1
	INSR	ENST00000341500.9	TSL:1	c.2806+88G>A		intron	N/A	ENSP00000342838.4	P06213-2
	INSR	ENST00000904791.1		c.2842+88G>A		intron	N/A	ENSP00000574850.1

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23843 AN: 151960 Hom.: 2250 Cov.: 31

Gnomad AFR AF: 0.262

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.0853

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.132

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.163

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.156

GnomAD4 exome AF: 0.115 AC: 157446 AN: 1372000 Hom.: 9868 AF XY: 0.115 AC XY: 78889 AN XY: 687054

African (AFR) AF: 0.271 AC: 8533 AN: 31520

American (AMR) AF: 0.0629 AC: 2804 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 3925 AN: 25530

East Asian (EAS) AF: 0.111 AC: 4338 AN: 39196

South Asian (SAS) AF: 0.129 AC: 10901 AN: 84258

European-Finnish (FIN) AF: 0.151 AC: 7963 AN: 52868

Middle Eastern (MID) AF: 0.172 AC: 968 AN: 5624

European-Non Finnish (NFE) AF: 0.108 AC: 110900 AN: 1030932

Other (OTH) AF: 0.124 AC: 7114 AN: 57464

GnomAD4 genome AF: 0.157 AC: 23864 AN: 152078 Hom.: 2251 Cov.: 31 AF XY: 0.154 AC XY: 11441 AN XY: 74320

African (AFR) AF: 0.262 AC: 10885 AN: 41478

American (AMR) AF: 0.0852 AC: 1303 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 544 AN: 3472

East Asian (EAS) AF: 0.131 AC: 677 AN: 5156

South Asian (SAS) AF: 0.125 AC: 601 AN: 4824

European-Finnish (FIN) AF: 0.144 AC: 1524 AN: 10550

Middle Eastern (MID) AF: 0.155 AC: 45 AN: 290

European-Non Finnish (NFE) AF: 0.115 AC: 7851 AN: 67996

Other (OTH) AF: 0.154 AC: 325 AN: 2112

Alfa AF: 0.100 Hom.: 197

Bravo AF: 0.156

Asia WGS AF: 0.115 AC: 401 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	-0.92
CADD	Benign	0.30
DANN	Benign	0.53
PhyloP100		-3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2860175; hg19: chr19-7132081; COSMIC: COSV107314500;