19-7184640-GGAGAGAGAGAGA-GGAGAGAGAGAGAGAGA

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BA1

The NM_000208.4(INSR):c.653-7_653-4dupTCTC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.044 ( 264 hom., cov: 0)

Exomes 𝑓: 0.0099 ( 135 hom. )

Consequence

INSR
NM_000208.4 splice_region, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:6

Conservation

PhyloP100: -2.04

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 -9 ACMG points.

BP6

Variant 19-7184640-G-GGAGA is Benign according to our data. Variant chr19-7184640-G-GGAGA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 330477.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=3}.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4 link	c.653-7_653-4dupTCTC	splice_region_variant, intron_variant	Intron 2 of 21	ENST00000302850.10	NP_000199.2	P06213-1
INSR	NM_001079817.3 link	c.653-7_653-4dupTCTC	splice_region_variant, intron_variant	Intron 2 of 20		NP_001073285.1	P06213-2
INSR	XM_011527988.3 link	c.653-7_653-4dupTCTC	splice_region_variant, intron_variant	Intron 2 of 21		XP_011526290.2
INSR	XM_011527989.4 link	c.653-7_653-4dupTCTC	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.653-4_653-3insTCTC	splice_region_variant, intron_variant	Intron 2 of 21	1	NM_000208.4	ENSP00000303830.4	P06213-1
INSR	ENST00000341500.9 link	c.653-4_653-3insTCTC	splice_region_variant, intron_variant	Intron 2 of 20	1		ENSP00000342838.4	P06213-2
INSR	ENST00000598216.1 link	n.628-4_628-3insTCTC	splice_region_variant, intron_variant	Intron 2 of 9	1

Frequencies

GnomAD3 genomes

AF:

0.0438

AC:

6228

AN:

142148

Hom.:

263

Cov.:

show subpopulations

Gnomad AFR

AF:

0.112

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0260

Gnomad ASJ

AF:

0.0265

Gnomad EAS

AF:

0.000400

Gnomad SAS

AF:

0.0331

Gnomad FIN

AF:

0.00382

Gnomad MID

AF:

0.0592

Gnomad NFE

AF:

0.0214

Gnomad OTH

AF:

0.0478

GnomAD3 exomes

AF:

0.0169

AC:

2329

AN:

137742

Hom.:

AF XY:

0.0181

AC XY:

1385

AN XY:

76688

show subpopulations

Gnomad AFR exome

AF:

0.0800

Gnomad AMR exome

AF:

0.00801

Gnomad ASJ exome

AF:

0.0228

Gnomad EAS exome

AF:

0.000399

Gnomad SAS exome

AF:

0.0295

Gnomad FIN exome

AF:

0.00313

Gnomad NFE exome

AF:

0.0146

Gnomad OTH exome

AF:

0.0142

GnomAD4 exome

AF:

0.00986

AC:

12158

AN:

1233004

Hom.:

135

Cov.:

AF XY:

0.0105

AC XY:

6490

AN XY:

617394

show subpopulations

Gnomad4 AFR exome

AF:

0.0610

Gnomad4 AMR exome

AF:

0.00880

Gnomad4 ASJ exome

AF:

0.0184

Gnomad4 EAS exome

AF:

0.000302

Gnomad4 SAS exome

AF:

0.0181

Gnomad4 FIN exome

AF:

0.00330

Gnomad4 NFE exome

AF:

0.00814

Gnomad4 OTH exome

AF:

0.0141

GnomAD4 genome

AF:

0.0439

AC:

6240

AN:

142238

Hom.:

264

Cov.:

AF XY:

0.0430

AC XY:

2968

AN XY:

68970

show subpopulations

Gnomad4 AFR

AF:

0.112

Gnomad4 AMR

AF:

0.0258

Gnomad4 ASJ

AF:

0.0265

Gnomad4 EAS

AF:

0.000401

Gnomad4 SAS

AF:

0.0334

Gnomad4 FIN

AF:

0.00382

Gnomad4 NFE

AF:

0.0214

Gnomad4 OTH

AF:

0.0474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Apr 09, 2018

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

Insulin-resistant diabetes mellitus AND acanthosis nigricans

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rabson-Mendenhall syndrome

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leprechaunism syndrome

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

May 14, 2022

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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