Genetic Variant INSR:c.2268-2530C>G (chr19-7145620-G-C) – 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.2268-2530C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0444 in 152,280 control chromosomes in the GnomAD database, including 907 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 0.044 ( 907 hom., cov: 33)

Consequence

INSR
NM_000208.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0820

Publications

1 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=-0.73).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.483 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4 link	c.2268-2530C>G	intron_variant	Intron 11 of 21	ENST00000302850.10	NP_000199.2	P06213-1
INSR	NM_001079817.3 link	c.2232-2530C>G	intron_variant	Intron 10 of 20		NP_001073285.1	P06213-2
INSR	XM_011527988.3 link	c.2268-2530C>G	intron_variant	Intron 11 of 21		XP_011526290.2
INSR	XM_011527989.4 link	c.2232-2530C>G	intron_variant	Intron 10 of 20		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10 link	c.2268-2530C>G		intron_variant	Intron 11 of 21	1	NM_000208.4	ENSP00000303830.4		P06213-1
INSR	ENST00000341500.9 link	c.2232-2530C>G		intron_variant	Intron 10 of 20	1		ENSP00000342838.4		P06213-2

Frequencies

GnomAD3 genomes

AF:

0.0443

AC:

6743

AN:

152164

Hom.:

903

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00827

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.166

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.498

Gnomad SAS

AF:

0.0591

Gnomad FIN

AF:

0.0608

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00390

Gnomad OTH

AF:

0.0334

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

GnomAD4 genome

AF:

0.0444

AC:

6759

AN:

152280

Hom.:

907

Cov.:

AF XY:

0.0525

AC XY:

3912

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.00835

AC:

347

AN:

41572

American (AMR)

AF:

0.167

AC:

2548

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

AN:

3470

East Asian (EAS)

AF:

0.499

AC:

2585

AN:

5180

South Asian (SAS)

AF:

0.0585

AC:

282

AN:

4820

European-Finnish (FIN)

AF:

0.0608

AC:

645

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00390

AC:

265

AN:

68024

Other (OTH)

AF:

0.0336

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

250

500

749

999

1249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

216

288

360

<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:

0.0200

Hom.:

Bravo

AF:

0.0537

Asia WGS

AF:

0.234

AC:

810

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

8.7

(source)

DANN

Benign

0.81

PhyloP100

0.082

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