Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_000208.4(INSR):c.2526G>C(p.Ala842Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0093 in 1,614,028 control chromosomes in the GnomAD database, including 162 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 48 hom., cov: 32)

Exomes 𝑓: 0.0083 ( 114 hom. )

Consequence

INSR
NM_000208.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.577

Publications

9 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.33).

BP6

Variant 19-7142832-C-G is Benign according to our data. Variant chr19-7142832-C-G is described in ClinVar as Benign. ClinVar VariationId is 330458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.577 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0184 (2803/152306) while in subpopulation AFR AF = 0.0437 (1816/41566). AF 95% confidence interval is 0.042. There are 48 homozygotes in GnomAd4. There are 1365 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 48 AR,AD gene

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.2526G>C	p.Ala842Ala	synonymous	Exon 12 of 22	NP_000199.2
	INSR	NM_001079817.3		c.2490G>C	p.Ala830Ala	synonymous	Exon 11 of 21	NP_001073285.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
INSR	ENST00000302850.10	TSL:1 MANE Select	c.2526G>C	p.Ala842Ala	synonymous	Exon 12 of 22	ENSP00000303830.4
INSR	ENST00000341500.9	TSL:1	c.2490G>C	p.Ala830Ala	synonymous	Exon 11 of 21	ENSP00000342838.4
INSR	ENST00000597211.1	TSL:3	n.209G>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.0183

AC:

2787

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0434

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00707

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.0416

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.00951

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00664

Gnomad OTH

AF:

0.0163

GnomAD2 exomes

AF:

0.0113

AC:

2826

AN:

249760

AF XY:

0.0100

show subpopulations

Gnomad AFR exome

AF:

0.0455

Gnomad AMR exome

AF:

0.00431

Gnomad ASJ exome

AF:

0.0118

Gnomad EAS exome

AF:

0.0394

Gnomad FIN exome

AF:

0.0102

Gnomad NFE exome

AF:

0.00674

Gnomad OTH exome

AF:

0.00981

GnomAD4 exome

AF:

0.00835

AC:

12201

AN:

1461722

Hom.:

114

Cov.:

AF XY:

0.00794

AC XY:

5777

AN XY:

727184

show subpopulations

African (AFR)

AF:

0.0426

AC:

1425

AN:

33480

American (AMR)

AF:

0.00465

AC:

208

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0130

AC:

339

AN:

26134

East Asian (EAS)

AF:

0.0419

AC:

1662

AN:

39698

South Asian (SAS)

AF:

0.00219

AC:

189

AN:

86256

European-Finnish (FIN)

AF:

0.0105

AC:

560

AN:

53284

Middle Eastern (MID)

AF:

0.00973

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00639

AC:

7106

AN:

1111998

Other (OTH)

AF:

0.0109

AC:

656

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

687

1374

2060

2747

3434

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

324

648

972

1296

1620

<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:

0.0184

AC:

2803

AN:

152306

Hom.:

Cov.:

AF XY:

0.0183

AC XY:

1365

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.0437

AC:

1816

AN:

41566

American (AMR)

AF:

0.00706

AC:

108

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0153

AC:

AN:

3468

East Asian (EAS)

AF:

0.0413

AC:

214

AN:

5184

South Asian (SAS)

AF:

0.00414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00951

AC:

101

AN:

10624

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00664

AC:

452

AN:

68026

Other (OTH)

AF:

0.0161

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

140

279

419

558

698

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.00724

Hom.:

Bravo

AF:

0.0200

Asia WGS

AF:

0.0230

AC:

AN:

3478

EpiCase

AF:

0.00518

EpiControl

AF:

0.00510

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Insulin-resistant diabetes mellitus AND acanthosis nigricans (1)

Leprechaunism syndrome (1)

Rabson-Mendenhall syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.33

CADD

Benign

6.4

(source)

DANN

Benign

0.73

PhyloP100

0.58

Mutation Taster

=100/0

polymorphism (auto)

(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

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

rs2229430

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over