rs121913145

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PP2PP3_StrongPP5_Moderate

The NM_000208.4(INSR):c.707A>G(p.His236Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

INSR
NM_000208.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.65

Publications

11 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: Likely_pathogenic. The variant received 7 ACMG points.

PP2

Missense variant in the INSR gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 3.8314 (above the threshold of 3.09). Trascript score misZ: 5.4593 (above the threshold of 3.09). GenCC associations: The gene is linked to Rabson-Mendenhall syndrome, hyperinsulinism due to INSR deficiency, Donohue syndrome, insulin-resistance syndrome type A.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.952

PP5

Variant 19-7184583-T-C is Pathogenic according to our data. Variant chr19-7184583-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 14693.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
INSR	NM_000208.4 link	c.707A>G	p.His236Arg	missense_variant	Exon 3 of 22	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3 link	c.707A>G	p.His236Arg	missense_variant	Exon 3 of 21		NP_001073285.1
INSR	XM_011527988.3 link	c.707A>G	p.His236Arg	missense_variant	Exon 3 of 22		XP_011526290.2
INSR	XM_011527989.4 link	c.707A>G	p.His236Arg	missense_variant	Exon 3 of 21		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
INSR	ENST00000302850.10 link	c.707A>G	p.His236Arg	missense_variant	Exon 3 of 22	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9 link	c.707A>G	p.His236Arg	missense_variant	Exon 3 of 21	1		ENSP00000342838.4
INSR	ENST00000598216.1 link	n.682A>G		non_coding_transcript_exon_variant	Exon 3 of 10	1

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151642

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000804

AC:

AN:

248690

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1461604

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727106

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53208

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0000234

AC:

AN:

1111978

Other (OTH)

AF:

0.0000828

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

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:

0.0000198

AC:

AN:

151642

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74032

show subpopulations

African (AFR)

AF:

0.0000243

AC:

AN:

41130

American (AMR)

AF:

0.00

AC:

AN:

15198

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10550

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67996

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.0000125

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Leprechaunism syndrome

Pathogenic:2

Nov 05, 1991

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Sep 05, 2014

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.41

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0

.;D

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

D;D

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Pathogenic

0.85

MutationAssessor

Pathogenic

4.2

H;H

PhyloP100

7.7

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-5.6

D;D

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0060

D;D

Vest4

0.80

ClinPred

0.99

GERP RS

5.0

Varity_R

0.93

gMVP

0.97

Mutation Taster

=9/91

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over