chr19-7163129-T-G

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.1932A>C(p.Pro644Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0937 in 1,612,524 control chromosomes in the GnomAD database, including 9,600 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1699 hom., cov: 31)

Exomes 𝑓: 0.090 ( 7901 hom. )

Consequence

INSR
NM_000208.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -2.75

Publications

17 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=-0.83).

BP6

Variant 19-7163129-T-G is Benign according to our data. Variant chr19-7163129-T-G is described in ClinVar as Benign. ClinVar VariationId is 330467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.75 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

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.1932A>C	p.Pro644Pro	synonymous	Exon 9 of 22	NP_000199.2
	INSR	NM_001079817.3		c.1932A>C	p.Pro644Pro	synonymous	Exon 9 of 21	NP_001073285.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
INSR	ENST00000302850.10	TSL:1 MANE Select	c.1932A>C	p.Pro644Pro	synonymous	Exon 9 of 22	ENSP00000303830.4
INSR	ENST00000341500.9	TSL:1	c.1932A>C	p.Pro644Pro	synonymous	Exon 9 of 21	ENSP00000342838.4
INSR	ENST00000598216.1	TSL:1	n.1907A>C		non_coding_transcript_exon	Exon 9 of 10

Frequencies

GnomAD3 genomes

AF:

0.126

AC:

19128

AN:

151700

Hom.:

1692

Cov.:

show subpopulations

Gnomad AFR

AF:

0.246

Gnomad AMI

AF:

0.157

Gnomad AMR

AF:

0.0830

Gnomad ASJ

AF:

0.0461

Gnomad EAS

AF:

0.0286

Gnomad SAS

AF:

0.245

Gnomad FIN

AF:

0.0390

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.0797

Gnomad OTH

AF:

0.119

GnomAD2 exomes

AF:

0.0985

AC:

24765

AN:

251480

AF XY:

0.104

show subpopulations

Gnomad AFR exome

AF:

0.244

Gnomad AMR exome

AF:

0.0601

Gnomad ASJ exome

AF:

0.0490

Gnomad EAS exome

AF:

0.0259

Gnomad FIN exome

AF:

0.0449

Gnomad NFE exome

AF:

0.0775

Gnomad OTH exome

AF:

0.0916

GnomAD4 exome

AF:

0.0904

AC:

131987

AN:

1460706

Hom.:

7901

Cov.:

AF XY:

0.0943

AC XY:

68512

AN XY:

726712

show subpopulations

African (AFR)

AF:

0.248

AC:

8286

AN:

33446

American (AMR)

AF:

0.0635

AC:

2838

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0482

AC:

1260

AN:

26136

East Asian (EAS)

AF:

0.0304

AC:

1208

AN:

39694

South Asian (SAS)

AF:

0.235

AC:

20222

AN:

86216

European-Finnish (FIN)

AF:

0.0454

AC:

2423

AN:

53412

Middle Eastern (MID)

AF:

0.115

AC:

660

AN:

5756

European-Non Finnish (NFE)

AF:

0.0803

AC:

89229

AN:

1110980

Other (OTH)

AF:

0.0971

AC:

5861

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.423

Heterozygous variant carriers

6872

13744

20616

27488

34360

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3506

7012

10518

14024

17530

<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:

0.126

AC:

19172

AN:

151818

Hom.:

1699

Cov.:

AF XY:

0.126

AC XY:

9322

AN XY:

74192

show subpopulations

African (AFR)

AF:

0.246

AC:

10166

AN:

41366

American (AMR)

AF:

0.0829

AC:

1261

AN:

15206

Ashkenazi Jewish (ASJ)

AF:

0.0461

AC:

160

AN:

3470

East Asian (EAS)

AF:

0.0285

AC:

147

AN:

5160

South Asian (SAS)

AF:

0.245

AC:

1177

AN:

4808

European-Finnish (FIN)

AF:

0.0390

AC:

412

AN:

10552

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0798

AC:

5419

AN:

67944

Other (OTH)

AF:

0.123

AC:

260

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

802

1604

2405

3207

4009

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

210

420

630

840

1050

<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:

0.0888

Hom.:

1057

Bravo

AF:

0.130

Asia WGS

AF:

0.186

AC:

648

AN:

3478

EpiCase

AF:

0.0816

EpiControl

AF:

0.0806

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

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

-0.83

CADD

Benign

0.18

(source)

DANN

Benign

0.62

PhyloP100

-2.8

Mutation Taster

=98/2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over