rs2229431

Positions:

• chr19-7141764-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.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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INSR	NM_000208.4	c.2595C>T	p.Asn865Asn	synonymous_variant	13/22	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.2559C>T	p.Asn853Asn	synonymous_variant	12/21		NP_001073285.1
INSR	XM_011527988.3	c.2595C>T	p.Asn865Asn	synonymous_variant	13/22		XP_011526290.2
INSR	XM_011527989.4	c.2559C>T	p.Asn853Asn	synonymous_variant	12/21		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.2595C>T	p.Asn865Asn	synonymous_variant	13/22	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.2559C>T	p.Asn853Asn	synonymous_variant	12/21	1		ENSP00000342838.4
INSR	ENST00000597211.1	n.278C>T		non_coding_transcript_exon_variant	2/2	3

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

GnomAD3 exomes AF: 0.0611 AC: 15360 AN: 251468 Hom.: 588 AF XY: 0.0586 AC XY: 7969 AN XY: 135908

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 SAS exome AF: 0.0447

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

Gnomad4 AFR exome AF: 0.156

Gnomad4 AMR exome AF: 0.0597

Gnomad4 ASJ exome AF: 0.0782

Gnomad4 EAS exome AF: 0.0932

Gnomad4 SAS exome AF: 0.0455

Gnomad4 FIN exome AF: 0.0687

Gnomad4 NFE exome AF: 0.0499

Gnomad4 OTH exome AF: 0.0588

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

Gnomad4 AFR AF: 0.155

Gnomad4 AMR AF: 0.0543

Gnomad4 ASJ AF: 0.0735

Gnomad4 EAS AF: 0.0783

Gnomad4 SAS AF: 0.0436

Gnomad4 FIN AF: 0.0730

Gnomad4 NFE AF: 0.0492

Gnomad4 OTH AF: 0.0851

Alfa AF: 0.0559 Hom.: 675

Bravo AF: 0.0858

Asia WGS AF: 0.0570 AC: 201 AN: 3478

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	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 04, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2021	- -

Insulin-resistant diabetes mellitus AND acanthosis nigricans Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 12, 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 12, 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	-0.80
CADD	Benign	1.0
DANN	Benign	0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs2229431; hg19: chr19-7141775; COSMIC: COSV57162764;