rs6510959

Positions:

• chr19-7184227-G-A

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.974+89C>T 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 1,174,158 control chromosomes in the GnomAD database, including 20,444 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3267 hom., cov: 29)
  • Exomes 𝑓: 0.18 (17177 hom.)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.756

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 19-7184227-G-A is Benign according to our data. Variant chr19-7184227-G-A is described in ClinVar as [Benign]. Clinvar id is 1229895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INSR	NM_000208.4	c.974+89C>T		intron_variant		ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.974+89C>T		intron_variant			NP_001073285.1
INSR	XM_011527988.3	c.974+89C>T		intron_variant			XP_011526290.2
INSR	XM_011527989.4	c.974+89C>T		intron_variant			XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.974+89C>T		intron_variant		1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.974+89C>T		intron_variant		1		ENSP00000342838.4
INSR	ENST00000598216.1	n.949+89C>T		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30745 AN: 151476 Hom.: 3252 Cov.: 29

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.0934

Gnomad AMR AF: 0.212

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.219

GnomAD4 exome AF: 0.179 AC: 183441 AN: 1022564 Hom.: 17177 AF XY: 0.180 AC XY: 93734 AN XY: 520676

Gnomad4 AFR exome AF: 0.261

Gnomad4 AMR exome AF: 0.233

Gnomad4 ASJ exome AF: 0.196

Gnomad4 EAS exome AF: 0.128

Gnomad4 SAS exome AF: 0.219

Gnomad4 FIN exome AF: 0.204

Gnomad4 NFE exome AF: 0.170

Gnomad4 OTH exome AF: 0.185

GnomAD4 genome AF: 0.203 AC: 30803 AN: 151594 Hom.: 3267 Cov.: 29 AF XY: 0.206 AC XY: 15233 AN XY: 74044

Gnomad4 AFR AF: 0.258

Gnomad4 AMR AF: 0.211

Gnomad4 ASJ AF: 0.197

Gnomad4 EAS AF: 0.118

Gnomad4 SAS AF: 0.219

Gnomad4 FIN AF: 0.217

Gnomad4 NFE AF: 0.172

Gnomad4 OTH AF: 0.219

Alfa AF: 0.191 Hom.: 367

Bravo AF: 0.205

Asia WGS AF: 0.188 AC: 653 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.061
DANN	Benign	0.86

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

LitVar

Other links and lift over

dbSNP: rs6510959; hg19: chr19-7184238; COSMIC: COSV57169425;