chr19-7184640-G-GGAGAGAGAGAGAGAGA

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000208.4(INSR):c.653-19_653-4dupTCTCTCTCTCTCTCTC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0000097 ( 0 hom. )

Consequence

INSR
NM_000208.4 splice_region, intron

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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: Uncertain_significance. The variant received 0 ACMG points.

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.653-19_653-4dupTCTCTCTCTCTCTCTC		splice_region intron	N/A	NP_000199.2
	INSR	NM_001079817.3		c.653-19_653-4dupTCTCTCTCTCTCTCTC		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_653-3insTCTCTCTCTCTCTCTC	splice_region intron	N/A	ENSP00000303830.4
INSR	ENST00000341500.9	TSL:1	c.653-4_653-3insTCTCTCTCTCTCTCTC	splice_region intron	N/A	ENSP00000342838.4
INSR	ENST00000598216.1	TSL:1	n.628-4_628-3insTCTCTCTCTCTCTCTC	splice_region intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000134

AC:

AN:

142296

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000523

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000972

AC:

AN:

1233944

Hom.:

Cov.:

AF XY:

0.00000971

AC XY:

AN XY:

617968

show subpopulations

African (AFR)

AF:

0.000322

AC:

AN:

24818

American (AMR)

AF:

0.000101

AC:

AN:

39560

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23124

East Asian (EAS)

AF:

0.00

AC:

AN:

36490

South Asian (SAS)

AF:

0.00

AC:

AN:

70478

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47250

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3920

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

937142

Other (OTH)

AF:

0.00

AC:

AN:

51162

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.404

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:

0.000133

AC:

AN:

142386

Hom.:

Cov.:

AF XY:

0.000116

AC XY:

AN XY:

69048

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000522

AC:

AN:

36398

American (AMR)

AF:

0.00

AC:

AN:

14296

Ashkenazi Jewish (ASJ)

AF:

0.00

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:

0.00

AC:

AN:

66288

Other (OTH)

AF:

0.00

AC:

AN:

1944

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000000000965894), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.343

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:

0.00

Hom.:

141

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Nov 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change falls in intron 2 of the INSR gene. It does not directly change the encoded amino acid sequence of the INSR protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with INSR-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the effect of this variant on mRNA splicing is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-2.0

Splicing

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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