rs891087

Variant names:

• chr19-7184507-G-A
• rs891087
• NM_000208.4:c.783C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-7184507-G-A
• chr19-7184507-G-C
• chr19-7184507-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000208.4(INSR):​c.783C>T​(p.Asp261Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0972 in 1,613,664 control chromosomes in the GnomAD database, including 8,822 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1311 hom., cov: 30)
  • Exomes 𝑓: 0.095 (7511 hom.)
• Consequence: INSR NM_000208.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.90
• Publications: 21 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 19-7184507-G-A is Benign according to our data. Variant chr19-7184507-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 330475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.9 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.197 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.783C>T	p.Asp261Asp	synonymous	Exon 3 of 22	NP_000199.2	P06213-1
	INSR	NM_001079817.3		c.783C>T	p.Asp261Asp	synonymous	Exon 3 of 21	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.783C>T	p.Asp261Asp	synonymous	Exon 3 of 22	ENSP00000303830.4	P06213-1
	INSR	ENST00000341500.9	TSL:1	c.783C>T	p.Asp261Asp	synonymous	Exon 3 of 21	ENSP00000342838.4	P06213-2
	INSR	ENST00000598216.1	TSL:1	n.758C>T		non_coding_transcript_exon	Exon 3 of 10

Frequencies

GnomAD3 genomes AF: 0.119 AC: 17993 AN: 151774 Hom.: 1303 Cov.: 30

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.199

Gnomad AMR AF: 0.0789

Gnomad ASJ AF: 0.0550

Gnomad EAS AF: 0.0422

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.0727

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0887

Gnomad OTH AF: 0.110

GnomAD2 exomes AF: 0.0973 AC: 24425 AN: 251000 AF XY: 0.101

Gnomad AFR exome AF: 0.204

Gnomad AMR exome AF: 0.0579

Gnomad ASJ exome AF: 0.0506

Gnomad EAS exome AF: 0.0406

Gnomad FIN exome AF: 0.0780

Gnomad NFE exome AF: 0.0881

Gnomad OTH exome AF: 0.0942

GnomAD4 exome AF: 0.0949 AC: 138791 AN: 1461772 Hom.: 7511 Cov.: 33 AF XY: 0.0970 AC XY: 70513 AN XY: 727180

African (AFR) AF: 0.202 AC: 6751 AN: 33478

American (AMR) AF: 0.0606 AC: 2710 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0510 AC: 1334 AN: 26134

East Asian (EAS) AF: 0.0532 AC: 2112 AN: 39700

South Asian (SAS) AF: 0.178 AC: 15383 AN: 86258

European-Finnish (FIN) AF: 0.0766 AC: 4088 AN: 53384

Middle Eastern (MID) AF: 0.105 AC: 607 AN: 5766

European-Non Finnish (NFE) AF: 0.0898 AC: 99868 AN: 1111938

Other (OTH) AF: 0.0983 AC: 5938 AN: 60392

GnomAD4 genome AF: 0.119 AC: 18029 AN: 151892 Hom.: 1311 Cov.: 30 AF XY: 0.119 AC XY: 8795 AN XY: 74214

African (AFR) AF: 0.200 AC: 8294 AN: 41376

American (AMR) AF: 0.0787 AC: 1199 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.0550 AC: 191 AN: 3472

East Asian (EAS) AF: 0.0421 AC: 218 AN: 5178

South Asian (SAS) AF: 0.182 AC: 872 AN: 4802

European-Finnish (FIN) AF: 0.0727 AC: 767 AN: 10554

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0887 AC: 6031 AN: 67966

Other (OTH) AF: 0.117 AC: 247 AN: 2108

Alfa AF: 0.0908 Hom.: 573

Bravo AF: 0.121

Asia WGS AF: 0.167 AC: 578 AN: 3478

EpiCase AF: 0.0885

EpiControl AF: 0.0873

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Insulin-resistant diabetes mellitus AND acanthosis nigricans (1)
-	-	1	Leprechaunism syndrome (1)
-	-	1	Leprechaunism syndrome;C0271695:Rabson-Mendenhall syndrome;C0342278:Insulin-resistant diabetes mellitus AND acanthosis nigricans;C1864952:Hyperinsulinism due to INSR deficiency (1)
-	-	1	not specified (1)
-	-	1	Rabson-Mendenhall syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	5.8
DANN	Benign	0.69
PhyloP100		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs891087; hg19: chr19-7184518; COSMIC: COSV57161309;