chr19-7184507-G-A

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.783C>T(p.Asp261Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0972 in 1,613,664 control chromosomes in the GnomAD database, including 8,822 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1311 hom., cov: 30)

Exomes 𝑓: 0.095 ( 7511 hom. )

Consequence

INSR
NM_000208.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.90

Publications

21 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=-0.73).

BP6

Variant 19-7184507-G-A is Benign according to our data. Variant chr19-7184507-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 330475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.9 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.197 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
INSR	NM_000208.4 link	c.783C>T	p.Asp261Asp	synonymous_variant	Exon 3 of 22	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3 link	c.783C>T	p.Asp261Asp	synonymous_variant	Exon 3 of 21		NP_001073285.1
INSR	XM_011527988.3 link	c.783C>T	p.Asp261Asp	synonymous_variant	Exon 3 of 22		XP_011526290.2
INSR	XM_011527989.4 link	c.783C>T	p.Asp261Asp	synonymous_variant	Exon 3 of 21		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
INSR	ENST00000302850.10 link	c.783C>T	p.Asp261Asp	synonymous_variant	Exon 3 of 22	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9 link	c.783C>T	p.Asp261Asp	synonymous_variant	Exon 3 of 21	1		ENSP00000342838.4
INSR	ENST00000598216.1 link	n.758C>T		non_coding_transcript_exon_variant	Exon 3 of 10	1

Frequencies

GnomAD3 genomes

AF:

0.119

AC:

17993

AN:

151774

Hom.:

1303

Cov.:

show subpopulations

Gnomad AFR

AF:

0.200

Gnomad AMI

AF:

0.199

Gnomad AMR

AF:

0.0789

Gnomad ASJ

AF:

0.0550

Gnomad EAS

AF:

0.0422

Gnomad SAS

AF:

0.182

Gnomad FIN

AF:

0.0727

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.0887

Gnomad OTH

AF:

0.110

GnomAD2 exomes

AF:

0.0973

AC:

24425

AN:

251000

AF XY:

0.101

show subpopulations

Gnomad AFR exome

AF:

0.204

Gnomad AMR exome

AF:

0.0579

Gnomad ASJ exome

AF:

0.0506

Gnomad EAS exome

AF:

0.0406

Gnomad FIN exome

AF:

0.0780

Gnomad NFE exome

AF:

0.0881

Gnomad OTH exome

AF:

0.0942

GnomAD4 exome

AF:

0.0949

AC:

138791

AN:

1461772

Hom.:

7511

Cov.:

AF XY:

0.0970

AC XY:

70513

AN XY:

727180

show subpopulations

African (AFR)

AF:

0.202

AC:

6751

AN:

33478

American (AMR)

AF:

0.0606

AC:

2710

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0510

AC:

1334

AN:

26134

East Asian (EAS)

AF:

0.0532

AC:

2112

AN:

39700

South Asian (SAS)

AF:

0.178

AC:

15383

AN:

86258

European-Finnish (FIN)

AF:

0.0766

AC:

4088

AN:

53384

Middle Eastern (MID)

AF:

0.105

AC:

607

AN:

5766

European-Non Finnish (NFE)

AF:

0.0898

AC:

99868

AN:

1111938

Other (OTH)

AF:

0.0983

AC:

5938

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

6688

13376

20064

26752

33440

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3812

7624

11436

15248

19060

<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:

0.119

AC:

18029

AN:

151892

Hom.:

1311

Cov.:

AF XY:

0.119

AC XY:

8795

AN XY:

74214

show subpopulations

African (AFR)

AF:

0.200

AC:

8294

AN:

41376

American (AMR)

AF:

0.0787

AC:

1199

AN:

15232

Ashkenazi Jewish (ASJ)

AF:

0.0550

AC:

191

AN:

3472

East Asian (EAS)

AF:

0.0421

AC:

218

AN:

5178

South Asian (SAS)

AF:

0.182

AC:

872

AN:

4802

European-Finnish (FIN)

AF:

0.0727

AC:

767

AN:

10554

Middle Eastern (MID)

AF:

0.0986

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0887

AC:

6031

AN:

67966

Other (OTH)

AF:

0.117

AC:

247

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

772

1545

2317

3090

3862

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

208

416

624

832

1040

<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:

0.0908

Hom.:

573

Bravo

AF:

0.121

Asia WGS

AF:

0.167

AC:

578

AN:

3478

EpiCase

AF:

0.0885

EpiControl

AF:

0.0873

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 14, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jan 26, 2018

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Leprechaunism syndrome;C0271695:Rabson-Mendenhall syndrome;C0342278:Insulin-resistant diabetes mellitus AND acanthosis nigricans;C1864952:Hyperinsulinism due to INSR deficiency

Benign:1

Sep 27, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Insulin-resistant diabetes mellitus AND acanthosis nigricans

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Rabson-Mendenhall syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Leprechaunism syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

5.8

(source)

DANN

Benign

0.69

PhyloP100

-1.9

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)

0.020

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