19-7166365-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000208.4(INSR):c.1650G>A(p.Ala550Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 1,613,598 control chromosomes in the GnomAD database, including 48,864 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4228 hom., cov: 31)

Exomes 𝑓: 0.24 ( 44636 hom. )

Consequence

INSR
NM_000208.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -4.84

Publications

44 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 19-7166365-C-T is Benign according to our data. Variant chr19-7166365-C-T is described in ClinVar as Benign. ClinVar VariationId is 198697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.84 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4 link	c.1650G>A	p.Ala550Ala	synonymous_variant	Exon 8 of 22	ENST00000302850.10	NP_000199.2	P06213-1
INSR	NM_001079817.3 link	c.1650G>A	p.Ala550Ala	synonymous_variant	Exon 8 of 21		NP_001073285.1	P06213-2
INSR	XM_011527988.3 link	c.1650G>A	p.Ala550Ala	synonymous_variant	Exon 8 of 22		XP_011526290.2
INSR	XM_011527989.4 link	c.1650G>A	p.Ala550Ala	synonymous_variant	Exon 8 of 21		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
INSR	ENST00000302850.10 link	c.1650G>A	p.Ala550Ala	synonymous_variant	Exon 8 of 22	1	NM_000208.4	ENSP00000303830.4	P06213-1
INSR	ENST00000341500.9 link	c.1650G>A	p.Ala550Ala	synonymous_variant	Exon 8 of 21	1		ENSP00000342838.4	P06213-2
INSR	ENST00000598216.1 link	n.1625G>A		non_coding_transcript_exon_variant	Exon 8 of 10	1
INSR	ENST00000600492.1 link	c.51G>A	p.Ala17Ala	synonymous_variant	Exon 2 of 4	5		ENSP00000473170.1	M0R3E6

Frequencies

GnomAD3 genomes

AF:

0.233

AC:

35453

AN:

151892

Hom.:

4223

Cov.:

show subpopulations

Gnomad AFR

AF:

0.184

Gnomad AMI

AF:

0.160

Gnomad AMR

AF:

0.238

Gnomad ASJ

AF:

0.311

Gnomad EAS

AF:

0.256

Gnomad SAS

AF:

0.273

Gnomad FIN

AF:

0.332

Gnomad MID

AF:

0.240

Gnomad NFE

AF:

0.238

Gnomad OTH

AF:

0.262

GnomAD2 exomes

AF:

0.256

AC:

64344

AN:

250902

AF XY:

0.258

show subpopulations

Gnomad AFR exome

AF:

0.186

Gnomad AMR exome

AF:

0.258

Gnomad ASJ exome

AF:

0.322

Gnomad EAS exome

AF:

0.250

Gnomad FIN exome

AF:

0.321

Gnomad NFE exome

AF:

0.248

Gnomad OTH exome

AF:

0.265

GnomAD4 exome

AF:

0.245

AC:

357816

AN:

1461588

Hom.:

44636

Cov.:

AF XY:

0.246

AC XY:

178559

AN XY:

727078

show subpopulations

African (AFR)

AF:

0.180

AC:

6016

AN:

33476

American (AMR)

AF:

0.254

AC:

11368

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.314

AC:

8206

AN:

26134

East Asian (EAS)

AF:

0.231

AC:

9158

AN:

39690

South Asian (SAS)

AF:

0.266

AC:

22915

AN:

86250

European-Finnish (FIN)

AF:

0.316

AC:

16864

AN:

53400

Middle Eastern (MID)

AF:

0.284

AC:

1636

AN:

5768

European-Non Finnish (NFE)

AF:

0.240

AC:

266624

AN:

1111802

Other (OTH)

AF:

0.249

AC:

15029

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

15562

31124

46687

62249

77811

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9136

18272

27408

36544

45680

<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:

0.233

AC:

35467

AN:

152010

Hom.:

4228

Cov.:

AF XY:

0.237

AC XY:

17615

AN XY:

74272

show subpopulations

African (AFR)

AF:

0.184

AC:

7649

AN:

41478

American (AMR)

AF:

0.238

AC:

3617

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.311

AC:

1079

AN:

3470

East Asian (EAS)

AF:

0.256

AC:

1323

AN:

5166

South Asian (SAS)

AF:

0.273

AC:

1318

AN:

4828

European-Finnish (FIN)

AF:

0.332

AC:

3503

AN:

10564

Middle Eastern (MID)

AF:

0.234

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.239

AC:

16214

AN:

67978

Other (OTH)

AF:

0.262

AC:

550

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1381

2762

4144

5525

6906

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

384

768

1152

1536

1920

<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:

0.235

Hom.:

6995

Bravo

AF:

0.223

Asia WGS

AF:

0.272

AC:

943

AN:

3478

EpiCase

AF:

0.243

EpiControl

AF:

0.252

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 10933564) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Rabson-Mendenhall syndrome

Benign:2

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 15, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Leprechaunism syndrome

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jan 28, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Insulin-resistant diabetes mellitus AND acanthosis nigricans

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.046

(source)

DANN

Benign

0.43

PhyloP100

-4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

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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