rs16994192

Positions:

• chr19-7141716-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000208.4(INSR):​c.2643C>T​(p.Ile881=) 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

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 330453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-7141716-G-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 49 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INSR	NM_000208.4	c.2643C>T	p.Ile881=	synonymous_variant	13/22	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.2607C>T	p.Ile869=	synonymous_variant	12/21		NP_001073285.1
INSR	XM_011527988.3	c.2643C>T	p.Ile881=	synonymous_variant	13/22		XP_011526290.2
INSR	XM_011527989.4	c.2607C>T	p.Ile869=	synonymous_variant	12/21		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.2643C>T	p.Ile881=	synonymous_variant	13/22	1	NM_000208.4	ENSP00000303830	A2
INSR	ENST00000341500.9	c.2607C>T	p.Ile869=	synonymous_variant	12/21	1		ENSP00000342838	P3
INSR	ENST00000597211.1	n.326C>T		non_coding_transcript_exon_variant	2/2	3

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

GnomAD3 exomes AF: 0.0113 AC: 2837 AN: 251482 Hom.: 43 AF XY: 0.0100 AC XY: 1361 AN XY: 135914

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 SAS exome AF: 0.00203

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

Gnomad4 AFR exome AF: 0.0427

Gnomad4 AMR exome AF: 0.00467

Gnomad4 ASJ exome AF: 0.0130

Gnomad4 EAS exome AF: 0.0418

Gnomad4 SAS exome AF: 0.00223

Gnomad4 FIN exome AF: 0.0105

Gnomad4 NFE exome AF: 0.00640

Gnomad4 OTH exome AF: 0.0109

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

Gnomad4 AFR AF: 0.0437

Gnomad4 AMR AF: 0.00719

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.0415

Gnomad4 SAS AF: 0.00415

Gnomad4 FIN AF: 0.00960

Gnomad4 NFE AF: 0.00664

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0117 Hom.: 14

Bravo AF: 0.0200

Asia WGS AF: 0.0230 AC: 80 AN: 3478

EpiCase AF: 0.00523

EpiControl AF: 0.00510

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2023	- -

Insulin-resistant diabetes mellitus AND acanthosis nigricans Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Rabson-Mendenhall syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hyperinsulinism due to INSR deficiency Benign:1

Likely benign, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Potent mutations in INSR gene can lead to insulin resistance, which presents as impaired glucose tolerance, early onset type 2 diabetes, post prandial hyperglycemia and increased insulin requirement in type 1 diabetes. These mutations in INSR gene can also predispose to coronary artery disease, metabolic syndrome, polycystic ovarian disease and non alcoholic fatty liver disease.However, the role of this particular variant rs2229432 with early onset diabetes mellitus is yet to be ascertained. -

Leprechaunism syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	0.35
DANN	Benign	0.78

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

Publications

LitVar

Other links and lift over

dbSNP: rs2229432; hg19: chr19-7141727; COSMIC: COSV57164935;