rs2245655

chr19-7163129-T-G

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.1932A>C(p.Pro644=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0937 in 1,612,524 control chromosomes in the GnomAD database, including 9,600 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1699 hom., cov: 31)
  • Exomes 𝑓: 0.090 (7901 hom.)
• Consequence: INSR NM_000208.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.75

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=-0.83).
• BP6: Variant 19-7163129-T-G is Benign according to our data. Variant chr19-7163129-T-G is described in ClinVar as [Benign]. Clinvar id is 330467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.75 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INSR	NM_000208.4	c.1932A>C	p.Pro644=	synonymous_variant	9/22	ENST00000302850.10
INSR	NM_001079817.3	c.1932A>C	p.Pro644=	synonymous_variant	9/21
INSR	XM_011527988.3	c.1932A>C	p.Pro644=	synonymous_variant	9/22
INSR	XM_011527989.4	c.1932A>C	p.Pro644=	synonymous_variant	9/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INSR	ENST00000302850.10	c.1932A>C	p.Pro644=	synonymous_variant	9/22	1	NM_000208.4	A2
INSR	ENST00000341500.9	c.1932A>C	p.Pro644=	synonymous_variant	9/21	1		P3
INSR	ENST00000598216.1	n.1907A>C		non_coding_transcript_exon_variant	9/10	1
INSR	ENST00000600492.1	c.333A>C	p.Pro111=	synonymous_variant	3/4	5

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19128 AN: 151700 Hom.: 1692 Cov.: 31

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.0830

Gnomad ASJ AF: 0.0461

Gnomad EAS AF: 0.0286

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.0390

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0797

Gnomad OTH AF: 0.119

GnomAD3 exomes AF: 0.0985 AC: 24765 AN: 251480 Hom.: 1927 AF XY: 0.104 AC XY: 14125 AN XY: 135918

Gnomad AFR exome AF: 0.244

Gnomad AMR exome AF: 0.0601

Gnomad ASJ exome AF: 0.0490

Gnomad EAS exome AF: 0.0259

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: 0.0904 AC: 131987 AN: 1460706 Hom.: 7901 Cov.: 32 AF XY: 0.0943 AC XY: 68512 AN XY: 726712

Gnomad4 AFR exome AF: 0.248

Gnomad4 AMR exome AF: 0.0635

Gnomad4 ASJ exome AF: 0.0482

Gnomad4 EAS exome AF: 0.0304

Gnomad4 SAS exome AF: 0.235

Gnomad4 FIN exome AF: 0.0454

Gnomad4 NFE exome AF: 0.0803

Gnomad4 OTH exome AF: 0.0971

GnomAD4 genome AF: 0.126 AC: 19172 AN: 151818 Hom.: 1699 Cov.: 31 AF XY: 0.126 AC XY: 9322 AN XY: 74192

Gnomad4 AFR AF: 0.246

Gnomad4 AMR AF: 0.0829

Gnomad4 ASJ AF: 0.0461

Gnomad4 EAS AF: 0.0285

Gnomad4 SAS AF: 0.245

Gnomad4 FIN AF: 0.0390

Gnomad4 NFE AF: 0.0798

Gnomad4 OTH AF: 0.123

Alfa AF: 0.0874 Hom.: 897

Bravo AF: 0.130

Asia WGS AF: 0.186 AC: 648 AN: 3478

EpiCase AF: 0.0816

EpiControl AF: 0.0806

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

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	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 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	-0.83
Cadd	Benign	0.18
Dann	Benign	0.62

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: rs2245655; hg19: chr19-7163140; COSMIC: COSV57157822;