Genetic Variant INSR:c.653-15_653-4dupTCTCTCTCTCTC (chr19-7184640-G-GGAGAGAGAGAGA) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_ModerateBS1

The NM_000208.4(INSR):c.653-15_653-4dupTCTCTCTCTCTC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00046 ( 1 hom., cov: 0)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

INSR
NM_000208.4 splice_region, intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.04

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP6

Variant 19-7184640-G-GGAGAGAGAGAGA is Benign according to our data. Variant chr19-7184640-G-GGAGAGAGAGAGA is described in ClinVar as [Likely_benign]. Clinvar id is 727146.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000457 (65/142360) while in subpopulation AFR AF= 0.00165 (60/36374). AF 95% confidence interval is 0.00132. There are 1 homozygotes in gnomad4. There are 29 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4 link	c.653-15_653-4dupTCTCTCTCTCTC	splice_region_variant, intron_variant	Intron 2 of 21	ENST00000302850.10	NP_000199.2	P06213-1
INSR	NM_001079817.3 link	c.653-15_653-4dupTCTCTCTCTCTC	splice_region_variant, intron_variant	Intron 2 of 20		NP_001073285.1	P06213-2
INSR	XM_011527988.3 link	c.653-15_653-4dupTCTCTCTCTCTC	splice_region_variant, intron_variant	Intron 2 of 21		XP_011526290.2
INSR	XM_011527989.4 link	c.653-15_653-4dupTCTCTCTCTCTC	splice_region_variant, intron_variant	Intron 2 of 20		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
INSR	ENST00000302850.10 link	c.653-4_653-3insTCTCTCTCTCTC	splice_region_variant, intron_variant	Intron 2 of 21	1	NM_000208.4	ENSP00000303830.4	P06213-1
INSR	ENST00000341500.9 link	c.653-4_653-3insTCTCTCTCTCTC	splice_region_variant, intron_variant	Intron 2 of 20	1		ENSP00000342838.4	P06213-2
INSR	ENST00000598216.1 link	n.628-4_628-3insTCTCTCTCTCTC	splice_region_variant, intron_variant	Intron 2 of 9	1

Frequencies

GnomAD3 genomes

AF:

0.000436

AC:

AN:

142270

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00157

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000140

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000302

Gnomad OTH

AF:

0.000519

GnomAD4 exome

AF:

0.0000122

AC:

AN:

1233940

Hom.:

Cov.:

AF XY:

0.0000129

AC XY:

AN XY:

617966

show subpopulations

Gnomad4 AFR exome

AF:

0.000483

Gnomad4 AMR exome

AF:

0.0000253

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000107

Gnomad4 OTH exome

AF:

0.0000195

GnomAD4 genome

AF:

0.000457

AC:

AN:

142360

Hom.:

Cov.:

AF XY:

0.000420

AC XY:

AN XY:

69036

show subpopulations

Gnomad4 AFR

AF:

0.00165

Gnomad4 AMR

AF:

0.000140

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000302

Gnomad4 OTH

AF:

0.000514

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Nov 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over