rs2229429

Positions:

• chr19-7166377-G-A
• chr19-7166377-G-C
• chr19-7166377-G-T

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.1638C>T​(p.Asp546=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 1,613,476 control chromosomes in the GnomAD database, including 37,173 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5966 hom., cov: 31)
  • Exomes 𝑓: 0.20 (31207 hom.)
• Consequence: INSR NM_000208.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.109

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=-0.53).
• BP6: Variant 19-7166377-G-A is Benign according to our data. Variant chr19-7166377-G-A is described in ClinVar as [Benign]. Clinvar id is 330470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.109 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.428 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INSR	NM_000208.4	c.1638C>T	p.Asp546=	synonymous_variant	8/22	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.1638C>T	p.Asp546=	synonymous_variant	8/21		NP_001073285.1
INSR	XM_011527988.3	c.1638C>T	p.Asp546=	synonymous_variant	8/22		XP_011526290.2
INSR	XM_011527989.4	c.1638C>T	p.Asp546=	synonymous_variant	8/21		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.1638C>T	p.Asp546=	synonymous_variant	8/22	1	NM_000208.4	ENSP00000303830	A2
INSR	ENST00000341500.9	c.1638C>T	p.Asp546=	synonymous_variant	8/21	1		ENSP00000342838	P3
INSR	ENST00000598216.1	n.1613C>T		non_coding_transcript_exon_variant	8/10	1
INSR	ENST00000600492.1	c.39C>T	p.Asp13=	synonymous_variant	2/4	5		ENSP00000473170

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38704 AN: 151828 Hom.: 5943 Cov.: 31

Gnomad AFR AF: 0.433

Gnomad AMI AF: 0.441

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.0653

Gnomad SAS AF: 0.270

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.255

GnomAD3 exomes AF: 0.197 AC: 49454 AN: 250726 Hom.: 5830 AF XY: 0.201 AC XY: 27217 AN XY: 135572

Gnomad AFR exome AF: 0.435

Gnomad AMR exome AF: 0.132

Gnomad ASJ exome AF: 0.224

Gnomad EAS exome AF: 0.0625

Gnomad SAS exome AF: 0.274

Gnomad FIN exome AF: 0.137

Gnomad NFE exome AF: 0.193

Gnomad OTH exome AF: 0.206

GnomAD4 exome AF: 0.199 AC: 290704 AN: 1461530 Hom.: 31207 Cov.: 36 AF XY: 0.201 AC XY: 146215 AN XY: 727082

Gnomad4 AFR exome AF: 0.442

Gnomad4 AMR exome AF: 0.139

Gnomad4 ASJ exome AF: 0.228

Gnomad4 EAS exome AF: 0.0601

Gnomad4 SAS exome AF: 0.270

Gnomad4 FIN exome AF: 0.137

Gnomad4 NFE exome AF: 0.195

Gnomad4 OTH exome AF: 0.213

GnomAD4 genome AF: 0.255 AC: 38779 AN: 151946 Hom.: 5966 Cov.: 31 AF XY: 0.252 AC XY: 18688 AN XY: 74272

Gnomad4 AFR AF: 0.433

Gnomad4 AMR AF: 0.180

Gnomad4 ASJ AF: 0.222

Gnomad4 EAS AF: 0.0648

Gnomad4 SAS AF: 0.269

Gnomad4 FIN AF: 0.134

Gnomad4 NFE AF: 0.195

Gnomad4 OTH AF: 0.260

Alfa AF: 0.200 Hom.: 2175

Bravo AF: 0.266

Asia WGS AF: 0.240 AC: 836 AN: 3478

EpiCase AF: 0.206

EpiControl AF: 0.206

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 24, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

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	-0.53
CADD	Benign	5.6
DANN	Benign	0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs2229429; hg19: chr19-7166388; COSMIC: COSV57158665;