19-7184640-GGAGAGAGAGAGA-GGAGAGAGAGA

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000208.4(INSR):c.653-5_653-4delTC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,315,650 control chromosomes in the GnomAD database, including 7,668 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1551 hom., cov: 0)

Exomes 𝑓: 0.13 ( 6117 hom. )

Consequence

INSR
NM_000208.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.176

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 19-7184640-GGA-G is Benign according to our data. Variant chr19-7184640-GGA-G is described in ClinVar as [Benign]. Clinvar id is 196236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-7184640-GGA-G is described in Lovd as [Benign]. Variant chr19-7184640-GGA-G is described in Lovd as [Likely_benign]. Variant chr19-7184640-GGA-G is described in Lovd as [Benign]. Variant chr19-7184640-GGA-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4 link	c.653-5_653-4delTC	splice_region_variant, intron_variant	Intron 2 of 21	ENST00000302850.10	NP_000199.2	P06213-1
INSR	NM_001079817.3 link	c.653-5_653-4delTC	splice_region_variant, intron_variant	Intron 2 of 20		NP_001073285.1	P06213-2
INSR	XM_011527988.3 link	c.653-5_653-4delTC	splice_region_variant, intron_variant	Intron 2 of 21		XP_011526290.2
INSR	XM_011527989.4 link	c.653-5_653-4delTC	splice_region_variant, intron_variant	Intron 2 of 20		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
INSR	ENST00000302850.10 link	c.653-5_653-4delTC	splice_region_variant, intron_variant	Intron 2 of 21	1	NM_000208.4	ENSP00000303830.4	P06213-1
INSR	ENST00000341500.9 link	c.653-5_653-4delTC	splice_region_variant, intron_variant	Intron 2 of 20	1		ENSP00000342838.4	P06213-2
INSR	ENST00000598216.1 link	n.628-5_628-4delTC	splice_region_variant, intron_variant	Intron 2 of 9	1

Frequencies

GnomAD3 genomes

AF:

0.137

AC:

19520

AN:

142016

Hom.:

1550

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0558

Gnomad AMI

AF:

0.0879

Gnomad AMR

AF:

0.182

Gnomad ASJ

AF:

0.193

Gnomad EAS

AF:

0.121

Gnomad SAS

AF:

0.198

Gnomad FIN

AF:

0.209

Gnomad MID

AF:

0.144

Gnomad NFE

AF:

0.157

Gnomad OTH

AF:

0.164

GnomAD3 exomes

AF:

0.238

AC:

32849

AN:

137742

Hom.:

1340

AF XY:

0.243

AC XY:

18641

AN XY:

76688

show subpopulations

Gnomad AFR exome

AF:

0.111

Gnomad AMR exome

AF:

0.245

Gnomad ASJ exome

AF:

0.258

Gnomad EAS exome

AF:

0.180

Gnomad SAS exome

AF:

0.237

Gnomad FIN exome

AF:

0.281

Gnomad NFE exome

AF:

0.249

Gnomad OTH exome

AF:

0.234

GnomAD4 exome

AF:

0.129

AC:

151247

AN:

1173544

Hom.:

6117

AF XY:

0.133

AC XY:

77709

AN XY:

584838

show subpopulations

Gnomad4 AFR exome

AF:

0.0445

Gnomad4 AMR exome

AF:

0.185

Gnomad4 ASJ exome

AF:

0.185

Gnomad4 EAS exome

AF:

0.157

Gnomad4 SAS exome

AF:

0.141

Gnomad4 FIN exome

AF:

0.195

Gnomad4 NFE exome

AF:

0.122

Gnomad4 OTH exome

AF:

0.136

GnomAD4 genome

AF:

0.137

AC:

19523

AN:

142106

Hom.:

1551

Cov.:

AF XY:

0.141

AC XY:

9736

AN XY:

68910

show subpopulations

Gnomad4 AFR

AF:

0.0558

Gnomad4 AMR

AF:

0.182

Gnomad4 ASJ

AF:

0.193

Gnomad4 EAS

AF:

0.121

Gnomad4 SAS

AF:

0.198

Gnomad4 FIN

AF:

0.209

Gnomad4 NFE

AF:

0.157

Gnomad4 OTH

AF:

0.164

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Jul 10, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 04, 2020

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:4

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 08, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Leprechaunism syndrome;C0271695:Rabson-Mendenhall syndrome;C0342278:Insulin-resistant diabetes mellitus AND acanthosis nigricans;C1864952:Hyperinsulinism due to INSR deficiency

Benign:1

Jan 24, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over