NM_000208.4:c.2643C>T

Variant names:

• chr19-7141716-G-A
• rs2229432
• NM_000208.4:c.2643C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000208.4(INSR):​c.2643C>T​(p.Ile881Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00931 in 1,614,070 control chromosomes in the GnomAD database, including 163 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (49 hom., cov: 31)
  • Exomes 𝑓: 0.0084 (114 hom.)
• Consequence: INSR NM_000208.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.12
• Publications: 7 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 19-7141716-G-A is Benign according to our data. Variant chr19-7141716-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 330453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.12 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0184 (2808/152274) while in subpopulation AFR AF = 0.0437 (1818/41564). AF 95% confidence interval is 0.0421. There are 49 homozygotes in GnomAd4. There are 1369 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 49 AR,AD gene

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.2643C>T	p.Ile881Ile	synonymous	Exon 13 of 22	NP_000199.2	P06213-1
	INSR	NM_001079817.3		c.2607C>T	p.Ile869Ile	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.2643C>T	p.Ile881Ile	synonymous	Exon 13 of 22	ENSP00000303830.4	P06213-1
	INSR	ENST00000341500.9	TSL:1	c.2607C>T	p.Ile869Ile	synonymous	Exon 12 of 21	ENSP00000342838.4	P06213-2
	INSR	ENST00000904791.1		c.2643C>T	p.Ile881Ile	synonymous	Exon 13 of 22	ENSP00000574850.1

Frequencies

GnomAD3 genomes AF: 0.0183 AC: 2792 AN: 152156 Hom.: 48 Cov.: 31

Gnomad AFR AF: 0.0434

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00720

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.0417

Gnomad SAS AF: 0.00415

Gnomad FIN AF: 0.00960

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00664

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.0113 AC: 2837 AN: 251482 AF XY: 0.0100

Gnomad AFR exome AF: 0.0457

Gnomad AMR exome AF: 0.00437

Gnomad ASJ exome AF: 0.0118

Gnomad EAS exome AF: 0.0391

Gnomad FIN exome AF: 0.0101

Gnomad NFE exome AF: 0.00672

Gnomad OTH exome AF: 0.00978

GnomAD4 exome AF: 0.00836 AC: 12215 AN: 1461796 Hom.: 114 Cov.: 31 AF XY: 0.00796 AC XY: 5786 AN XY: 727200

African (AFR) AF: 0.0427 AC: 1428 AN: 33478

American (AMR) AF: 0.00467 AC: 209 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 341 AN: 26136

East Asian (EAS) AF: 0.0418 AC: 1658 AN: 39700

South Asian (SAS) AF: 0.00223 AC: 192 AN: 86254

European-Finnish (FIN) AF: 0.0105 AC: 562 AN: 53418

Middle Eastern (MID) AF: 0.00971 AC: 56 AN: 5768

European-Non Finnish (NFE) AF: 0.00640 AC: 7113 AN: 1111924

Other (OTH) AF: 0.0109 AC: 656 AN: 60394

GnomAD4 genome AF: 0.0184 AC: 2808 AN: 152274 Hom.: 49 Cov.: 31 AF XY: 0.0184 AC XY: 1369 AN XY: 74460

African (AFR) AF: 0.0437 AC: 1818 AN: 41564

American (AMR) AF: 0.00719 AC: 110 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3472

East Asian (EAS) AF: 0.0415 AC: 214 AN: 5162

South Asian (SAS) AF: 0.00415 AC: 20 AN: 4820

European-Finnish (FIN) AF: 0.00960 AC: 102 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00664 AC: 452 AN: 68028

Other (OTH) AF: 0.0161 AC: 34 AN: 2110

Alfa AF: 0.0114 Hom.: 16

Bravo AF: 0.0200

Asia WGS AF: 0.0230 AC: 80 AN: 3478

EpiCase AF: 0.00523

EpiControl AF: 0.00510

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hyperinsulinism due to INSR deficiency (1)
-	-	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	-0.29
CADD	Benign	0.35
DANN	Benign	0.78
PhyloP100		-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: rs2229432; hg19: chr19-7141727; COSMIC: COSV57164935;