rs2245649

chr19-7163203-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000208.4(INSR):c.1862-4A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0909 in 1,602,380 control chromosomes in the GnomAD database, including 9,322 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1700 hom., cov: 30)
  • Exomes 𝑓: 0.087 (7622 hom.)
• Consequence: INSR NM_000208.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001008
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.40

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 19-7163203-T-C is Benign according to our data. Variant chr19-7163203-T-C is described in ClinVar as [Benign]. Clinvar id is 330469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.241 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INSR	NM_000208.4	c.1862-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000302850.10
INSR	NM_001079817.3	c.1862-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
INSR	XM_011527988.3	c.1862-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
INSR	XM_011527989.4	c.1862-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INSR	ENST00000302850.10	c.1862-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000208.4	A2
INSR	ENST00000341500.9	c.1862-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		P3
INSR	ENST00000598216.1	n.1837-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		1
INSR	ENST00000600492.1	c.263-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19104 AN: 151808 Hom.: 1693 Cov.: 30

Gnomad AFR AF: 0.245

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.0829

Gnomad ASJ AF: 0.0461

Gnomad EAS AF: 0.0284

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.0387

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0796

Gnomad OTH AF: 0.118

GnomAD3 exomes AF: 0.0983 AC: 24702 AN: 251252 Hom.: 1917 AF XY: 0.104 AC XY: 14102 AN XY: 135816

Gnomad AFR exome AF: 0.243

Gnomad AMR exome AF: 0.0601

Gnomad ASJ exome AF: 0.0490

Gnomad EAS exome AF: 0.0259

Gnomad SAS exome AF: 0.241

Gnomad FIN exome AF: 0.0449

Gnomad NFE exome AF: 0.0774

Gnomad OTH exome AF: 0.0917

GnomAD4 exome AF: 0.0873 AC: 126575 AN: 1450454 Hom.: 7622 Cov.: 31 AF XY: 0.0915 AC XY: 66083 AN XY: 722058

Gnomad4 AFR exome AF: 0.242

Gnomad4 AMR exome AF: 0.0633

Gnomad4 ASJ exome AF: 0.0474

Gnomad4 EAS exome AF: 0.0302

Gnomad4 SAS exome AF: 0.233

Gnomad4 FIN exome AF: 0.0453

Gnomad4 NFE exome AF: 0.0768

Gnomad4 OTH exome AF: 0.0945

GnomAD4 genome AF: 0.126 AC: 19148 AN: 151926 Hom.: 1700 Cov.: 30 AF XY: 0.125 AC XY: 9314 AN XY: 74256

Gnomad4 AFR AF: 0.245

Gnomad4 AMR AF: 0.0828

Gnomad4 ASJ AF: 0.0461

Gnomad4 EAS AF: 0.0282

Gnomad4 SAS AF: 0.244

Gnomad4 FIN AF: 0.0387

Gnomad4 NFE AF: 0.0796

Gnomad4 OTH AF: 0.123

Alfa AF: 0.0983 Hom.: 540

Bravo AF: 0.130

Asia WGS AF: 0.187 AC: 651 AN: 3478

EpiCase AF: 0.0816

EpiControl AF: 0.0806

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 14, 2021	- -

Insulin-resistant diabetes mellitus AND acanthosis nigricans Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

Leprechaunism syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.64
Dann	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00010
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2245649; hg19: chr19-7163214; COSMIC: COSV57159596;