rs2229431

Variant names:

• chr19-7141764-G-A
• rs2229431
• NM_000208.4:c.2595C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-7141764-G-A
• chr19-7141764-G-C
• chr19-7141764-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.2595C>T​(p.Asn865Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0577 in 1,614,032 control chromosomes in the GnomAD database, including 3,258 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (715 hom., cov: 31)
  • Exomes 𝑓: 0.055 (2543 hom.)
• Consequence: INSR NM_000208.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.753
• 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=-0.8).
• BP6: Variant 19-7141764-G-A is Benign according to our data. Variant chr19-7141764-G-A is described in ClinVar as Benign. ClinVar VariationId is 330454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.753 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.152 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.2595C>T	p.Asn865Asn	synonymous	Exon 13 of 22	NP_000199.2	P06213-1
	INSR	NM_001079817.3		c.2559C>T	p.Asn853Asn	synonymous	Exon 12 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.2595C>T	p.Asn865Asn	synonymous	Exon 13 of 22	ENSP00000303830.4	P06213-1
	INSR	ENST00000341500.9	TSL:1	c.2559C>T	p.Asn853Asn	synonymous	Exon 12 of 21	ENSP00000342838.4	P06213-2
	INSR	ENST00000904791.1		c.2595C>T	p.Asn865Asn	synonymous	Exon 13 of 22	ENSP00000574850.1

Frequencies

GnomAD3 genomes AF: 0.0822 AC: 12499 AN: 152112 Hom.: 713 Cov.: 31

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.0542

Gnomad ASJ AF: 0.0735

Gnomad EAS AF: 0.0781

Gnomad SAS AF: 0.0435

Gnomad FIN AF: 0.0730

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0493

Gnomad OTH AF: 0.0860

GnomAD2 exomes AF: 0.0611 AC: 15360 AN: 251468 AF XY: 0.0586

Gnomad AFR exome AF: 0.157

Gnomad AMR exome AF: 0.0604

Gnomad ASJ exome AF: 0.0785

Gnomad EAS exome AF: 0.0688

Gnomad FIN exome AF: 0.0703

Gnomad NFE exome AF: 0.0476

Gnomad OTH exome AF: 0.0580

GnomAD4 exome AF: 0.0552 AC: 80646 AN: 1461802 Hom.: 2543 Cov.: 32 AF XY: 0.0545 AC XY: 39658 AN XY: 727192

African (AFR) AF: 0.156 AC: 5221 AN: 33470

American (AMR) AF: 0.0597 AC: 2669 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0782 AC: 2045 AN: 26136

East Asian (EAS) AF: 0.0932 AC: 3701 AN: 39700

South Asian (SAS) AF: 0.0455 AC: 3926 AN: 86258

European-Finnish (FIN) AF: 0.0687 AC: 3670 AN: 53418

Middle Eastern (MID) AF: 0.0659 AC: 380 AN: 5768

European-Non Finnish (NFE) AF: 0.0499 AC: 55482 AN: 1111932

Other (OTH) AF: 0.0588 AC: 3552 AN: 60396

GnomAD4 genome AF: 0.0822 AC: 12514 AN: 152230 Hom.: 715 Cov.: 31 AF XY: 0.0832 AC XY: 6195 AN XY: 74418

African (AFR) AF: 0.155 AC: 6450 AN: 41544

American (AMR) AF: 0.0543 AC: 830 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0735 AC: 255 AN: 3468

East Asian (EAS) AF: 0.0783 AC: 404 AN: 5162

South Asian (SAS) AF: 0.0436 AC: 210 AN: 4820

European-Finnish (FIN) AF: 0.0730 AC: 774 AN: 10604

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0492 AC: 3348 AN: 68020

Other (OTH) AF: 0.0851 AC: 180 AN: 2114

Alfa AF: 0.0600 Hom.: 1473

Bravo AF: 0.0858

Asia WGS AF: 0.0570 AC: 201 AN: 3478

ClinVar

ClinVar submissions

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	-0.80
CADD	Benign	1.0
DANN	Benign	0.54
PhyloP100		-0.75
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)		0.010		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: rs2229431; hg19: chr19-7141775; COSMIC: COSV57162764;