rs2963

Positions:

• chr19-7163143-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000208.4(INSR):​c.1918C>T​(p.Leu640=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0933 in 1,611,114 control chromosomes in the GnomAD database, including 9,582 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1698 hom., cov: 31)
  • Exomes 𝑓: 0.090 (7884 hom.)
• Consequence: INSR NM_000208.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0530

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 19-7163143-G-A is Benign according to our data. Variant chr19-7163143-G-A is described in ClinVar as [Benign]. Clinvar id is 330468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.053 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.241 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INSR	NM_000208.4	c.1918C>T	p.Leu640=	synonymous_variant	9/22	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.1918C>T	p.Leu640=	synonymous_variant	9/21		NP_001073285.1
INSR	XM_011527988.3	c.1918C>T	p.Leu640=	synonymous_variant	9/22		XP_011526290.2
INSR	XM_011527989.4	c.1918C>T	p.Leu640=	synonymous_variant	9/21		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.1918C>T	p.Leu640=	synonymous_variant	9/22	1	NM_000208.4	ENSP00000303830	A2
INSR	ENST00000341500.9	c.1918C>T	p.Leu640=	synonymous_variant	9/21	1		ENSP00000342838	P3
INSR	ENST00000598216.1	n.1893C>T		non_coding_transcript_exon_variant	9/10	1
INSR	ENST00000600492.1	c.319C>T	p.Leu107=	synonymous_variant	3/4	5		ENSP00000473170

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19121 AN: 151966 Hom.: 1691 Cov.: 31

Gnomad AFR AF: 0.245

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.0827

Gnomad ASJ AF: 0.0461

Gnomad EAS AF: 0.0283

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.0389

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0797

Gnomad OTH AF: 0.119

GnomAD3 exomes AF: 0.0984 AC: 24751 AN: 251456 Hom.: 1925 AF XY: 0.104 AC XY: 14120 AN XY: 135910

Gnomad AFR exome AF: 0.244

Gnomad AMR exome AF: 0.0601

Gnomad ASJ exome AF: 0.0490

Gnomad EAS exome AF: 0.0258

Gnomad SAS exome AF: 0.241

Gnomad FIN exome AF: 0.0449

Gnomad NFE exome AF: 0.0775

Gnomad OTH exome AF: 0.0916

GnomAD4 exome AF: 0.0899 AC: 131098 AN: 1459030 Hom.: 7884 Cov.: 32 AF XY: 0.0938 AC XY: 68101 AN XY: 725942

Gnomad4 AFR exome AF: 0.247

Gnomad4 AMR exome AF: 0.0634

Gnomad4 ASJ exome AF: 0.0481

Gnomad4 EAS exome AF: 0.0304

Gnomad4 SAS exome AF: 0.234

Gnomad4 FIN exome AF: 0.0454

Gnomad4 NFE exome AF: 0.0797

Gnomad4 OTH exome AF: 0.0967

GnomAD4 genome AF: 0.126 AC: 19165 AN: 152084 Hom.: 1698 Cov.: 31 AF XY: 0.125 AC XY: 9318 AN XY: 74344

Gnomad4 AFR AF: 0.245

Gnomad4 AMR AF: 0.0826

Gnomad4 ASJ AF: 0.0461

Gnomad4 EAS AF: 0.0282

Gnomad4 SAS AF: 0.244

Gnomad4 FIN AF: 0.0389

Gnomad4 NFE AF: 0.0797

Gnomad4 OTH AF: 0.123

Alfa AF: 0.0885 Hom.: 966

Bravo AF: 0.130

Asia WGS AF: 0.187 AC: 651 AN: 3478

EpiCase AF: 0.0816

EpiControl AF: 0.0806

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

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. -

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	-0.79
CADD	Benign	0.057
DANN	Benign	0.61

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: rs2963; hg19: chr19-7163154; COSMIC: COSV57157833;