chr19-7184640-G-GGAGAGA

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_StrongBS1

The NM_000208.4(INSR):c.653-9_653-4dupTCTCTC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

INSR
NM_000208.4 splice_region, intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -2.04

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

insulin-resistance syndrome type A
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P
Donohue syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
hyperinsulinism due to INSR deficiency
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, Ambry Genetics
Rabson-Mendenhall syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

INSR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP6

Variant 19-7184640-G-GGAGAGA is Benign according to our data. Variant chr19-7184640-G-GGAGAGA is described in ClinVar as Likely_benign. ClinVar VariationId is 1336488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.000128 (158/1233896) while in subpopulation AFR AF = 0.00121 (30/24812). AF 95% confidence interval is 0.00087. There are 1 homozygotes in GnomAdExome4. There are 89 alleles in the male GnomAdExome4 subpopulation. Median coverage is 17. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000208.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	NM_000208.4	MANE Select	c.653-9_653-4dupTCTCTC		splice_region intron	N/A	NP_000199.2
	INSR	NM_001079817.3		c.653-9_653-4dupTCTCTC		splice_region intron	N/A	NP_001073285.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
INSR	ENST00000302850.10	TSL:1 MANE Select	c.653-4_653-3insTCTCTC	splice_region intron	N/A	ENSP00000303830.4
INSR	ENST00000341500.9	TSL:1	c.653-4_653-3insTCTCTC	splice_region intron	N/A	ENSP00000342838.4
INSR	ENST00000598216.1	TSL:1	n.628-4_628-3insTCTCTC	splice_region intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000162

AC:

AN:

142298

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000110

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00353

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000106

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000479

AC:

AN:

137742

AF XY:

0.000443

show subpopulations

Gnomad AFR exome

AF:

0.00342

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00163

Gnomad EAS exome

AF:

0.00140

Gnomad FIN exome

AF:

0.000161

Gnomad NFE exome

AF:

0.000131

Gnomad OTH exome

AF:

0.000289

GnomAD4 exome

AF:

0.000128

AC:

158

AN:

1233896

Hom.:

Cov.:

AF XY:

0.000144

AC XY:

AN XY:

617932

show subpopulations

African (AFR)

AF:

0.00121

AC:

AN:

24812

American (AMR)

AF:

0.000152

AC:

AN:

39554

Ashkenazi Jewish (ASJ)

AF:

0.00151

AC:

AN:

23116

East Asian (EAS)

AF:

0.000466

AC:

AN:

36484

South Asian (SAS)

AF:

0.000170

AC:

AN:

70476

European-Finnish (FIN)

AF:

0.0000635

AC:

AN:

47250

Middle Eastern (MID)

AF:

0.000765

AC:

AN:

3920

European-Non Finnish (NFE)

AF:

0.0000395

AC:

AN:

937128

Other (OTH)

AF:

0.000293

AC:

AN:

51156

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.423

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000162

AC:

AN:

142388

Hom.:

Cov.:

AF XY:

0.0000724

AC XY:

AN XY:

69050

show subpopulations

African (AFR)

AF:

0.000110

AC:

AN:

36400

American (AMR)

AF:

0.00

AC:

AN:

14296

Ashkenazi Jewish (ASJ)

AF:

0.00353

AC:

AN:

3404

East Asian (EAS)

AF:

0.00

AC:

AN:

4986

South Asian (SAS)

AF:

0.00

AC:

AN:

4496

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.000106

AC:

AN:

66288

Other (OTH)

AF:

0.00

AC:

AN:

1944

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000386

Hom.:

141

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Dec 18, 2018

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

INSR-related disorder

Benign:1

Dec 27, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-2.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over