chr19-7163054-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000208.4(INSR):c.2007C>T(p.Phe669Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0714 in 1,613,450 control chromosomes in the GnomAD database, including 4,490 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.081 ( 573 hom., cov: 30)

Exomes 𝑓: 0.070 ( 3917 hom. )

Consequence

INSR
NM_000208.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.0430

Publications

36 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=-0.43).

BP6

Variant 19-7163054-G-A is Benign according to our data. Variant chr19-7163054-G-A is described in ClinVar as Benign. ClinVar VariationId is 330466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.043 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4 link	c.2007C>T	p.Phe669Phe	synonymous_variant	Exon 9 of 22	ENST00000302850.10	NP_000199.2	P06213-1
INSR	NM_001079817.3 link	c.2007C>T	p.Phe669Phe	synonymous_variant	Exon 9 of 21		NP_001073285.1	P06213-2
INSR	XM_011527988.3 link	c.2007C>T	p.Phe669Phe	synonymous_variant	Exon 9 of 22		XP_011526290.2
INSR	XM_011527989.4 link	c.2007C>T	p.Phe669Phe	synonymous_variant	Exon 9 of 21		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
INSR	ENST00000302850.10 link	c.2007C>T	p.Phe669Phe	synonymous_variant	Exon 9 of 22	1	NM_000208.4	ENSP00000303830.4	P06213-1
INSR	ENST00000341500.9 link	c.2007C>T	p.Phe669Phe	synonymous_variant	Exon 9 of 21	1		ENSP00000342838.4	P06213-2
INSR	ENST00000598216.1 link	n.1982C>T		non_coding_transcript_exon_variant	Exon 9 of 10	1
INSR	ENST00000600492.1 link	c.408C>T	p.Phe136Phe	synonymous_variant	Exon 3 of 4	5		ENSP00000473170.1	M0R3E6

Frequencies

GnomAD3 genomes

AF:

0.0807

AC:

12252

AN:

151834

Hom.:

574

Cov.:

show subpopulations

Gnomad AFR

AF:

0.113

Gnomad AMI

AF:

0.211

Gnomad AMR

AF:

0.0526

Gnomad ASJ

AF:

0.0605

Gnomad EAS

AF:

0.0257

Gnomad SAS

AF:

0.0425

Gnomad FIN

AF:

0.0682

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0764

Gnomad OTH

AF:

0.0644

GnomAD2 exomes

AF:

0.0643

AC:

16169

AN:

251466

AF XY:

0.0638

show subpopulations

Gnomad AFR exome

AF:

0.113

Gnomad AMR exome

AF:

0.0412

Gnomad ASJ exome

AF:

0.0646

Gnomad EAS exome

AF:

0.0261

Gnomad FIN exome

AF:

0.0650

Gnomad NFE exome

AF:

0.0744

Gnomad OTH exome

AF:

0.0682

GnomAD4 exome

AF:

0.0704

AC:

102916

AN:

1461498

Hom.:

3917

Cov.:

AF XY:

0.0697

AC XY:

50654

AN XY:

727054

show subpopulations

African (AFR)

AF:

0.111

AC:

3701

AN:

33462

American (AMR)

AF:

0.0440

AC:

1969

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0660

AC:

1725

AN:

26134

East Asian (EAS)

AF:

0.0218

AC:

864

AN:

39694

South Asian (SAS)

AF:

0.0468

AC:

4032

AN:

86238

European-Finnish (FIN)

AF:

0.0635

AC:

3389

AN:

53402

Middle Eastern (MID)

AF:

0.0506

AC:

283

AN:

5598

European-Non Finnish (NFE)

AF:

0.0743

AC:

82603

AN:

1111892

Other (OTH)

AF:

0.0721

AC:

4350

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

5489

10979

16468

21958

27447

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3016

6032

9048

12064

15080

<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:

0.0807

AC:

12260

AN:

151952

Hom.:

573

Cov.:

AF XY:

0.0786

AC XY:

5837

AN XY:

74252

show subpopulations

African (AFR)

AF:

0.113

AC:

4664

AN:

41444

American (AMR)

AF:

0.0525

AC:

800

AN:

15228

Ashkenazi Jewish (ASJ)

AF:

0.0605

AC:

210

AN:

3472

East Asian (EAS)

AF:

0.0256

AC:

132

AN:

5160

South Asian (SAS)

AF:

0.0429

AC:

207

AN:

4822

European-Finnish (FIN)

AF:

0.0682

AC:

720

AN:

10558

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0764

AC:

5192

AN:

67960

Other (OTH)

AF:

0.0642

AC:

135

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

566

1133

1699

2266

2832

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

142

284

426

568

710

<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:

0.0767

Hom.:

512

Bravo

AF:

0.0815

Asia WGS

AF:

0.0450

AC:

155

AN:

3478

EpiCase

AF:

0.0738

EpiControl

AF:

0.0767

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 24, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

-0.43

CADD

Benign

0.32

(source)

DANN

Benign

0.83

PhyloP100

-0.043

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