dbSNP rs2860174: INSR:c.2842+1451T>A (chr19-7130707-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000208.4(INSR):c.2842+1451T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 152,060 control chromosomes in the GnomAD database, including 2,640 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.18 ( 2640 hom., cov: 31)

Consequence

INSR
NM_000208.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.316

Publications

2 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4 link	c.2842+1451T>A	intron_variant	Intron 14 of 21	ENST00000302850.10	NP_000199.2	P06213-1
INSR	NM_001079817.3 link	c.2806+1451T>A	intron_variant	Intron 13 of 20		NP_001073285.1	P06213-2
INSR	XM_011527988.3 link	c.2842+1451T>A	intron_variant	Intron 14 of 21		XP_011526290.2
INSR	XM_011527989.4 link	c.2806+1451T>A	intron_variant	Intron 13 of 20		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10 link	c.2842+1451T>A		intron_variant	Intron 14 of 21	1	NM_000208.4	ENSP00000303830.4		P06213-1
INSR	ENST00000341500.9 link	c.2806+1451T>A		intron_variant	Intron 13 of 20	1		ENSP00000342838.4		P06213-2

Frequencies

GnomAD3 genomes

AF:

0.182

AC:

27666

AN:

151940

Hom.:

2643

Cov.:

show subpopulations

Gnomad AFR

AF:

0.195

Gnomad AMI

AF:

0.115

Gnomad AMR

AF:

0.145

Gnomad ASJ

AF:

0.160

Gnomad EAS

AF:

0.148

Gnomad SAS

AF:

0.307

Gnomad FIN

AF:

0.178

Gnomad MID

AF:

0.277

Gnomad NFE

AF:

0.178

Gnomad OTH

AF:

0.187

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.182

AC:

27681

AN:

152060

Hom.:

2640

Cov.:

AF XY:

0.182

AC XY:

13534

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.195

AC:

8092

AN:

41474

American (AMR)

AF:

0.144

AC:

2205

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.160

AC:

555

AN:

3470

East Asian (EAS)

AF:

0.148

AC:

764

AN:

5170

South Asian (SAS)

AF:

0.306

AC:

1473

AN:

4806

European-Finnish (FIN)

AF:

0.178

AC:

1883

AN:

10576

Middle Eastern (MID)

AF:

0.276

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.178

AC:

12124

AN:

67982

Other (OTH)

AF:

0.190

AC:

400

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1123

2245

3368

4490

5613

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

310

620

930

1240

1550

<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:

0.177

Hom.:

325

Bravo

AF:

0.178

Asia WGS

AF:

0.207

AC:

720

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

2.0

(source)

DANN

Benign

0.51

PhyloP100

0.32

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over