19-7134002-C-T

Variant names:

• chr19-7134002-C-T
• rs10420382
• NM_000208.4:c.2683-1685G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000208.4(INSR):​c.2683-1685G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 152,010 control chromosomes in the GnomAD database, including 3,389 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 (3389 hom., cov: 33)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.58
• Publications: 4 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.483 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000208.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	NM_000208.4	MANE Select	c.2683-1685G>A		intron	N/A	NP_000199.2
	INSR	NM_001079817.3		c.2647-1685G>A		intron	N/A	NP_001073285.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	ENST00000302850.10	TSL:1 MANE Select	c.2683-1685G>A		intron	N/A	ENSP00000303830.4
	INSR	ENST00000341500.9	TSL:1	c.2647-1685G>A		intron	N/A	ENSP00000342838.4
	INSR	ENST00000904791.1		c.2683-1685G>A		intron	N/A	ENSP00000574850.1

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27322 AN: 151892 Hom.: 3376 Cov.: 33

Gnomad AFR AF: 0.288

Gnomad AMI AF: 0.219

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.498

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.0864

Gnomad OTH AF: 0.175

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

GnomAD4 genome AF: 0.180 AC: 27376 AN: 152010 Hom.: 3389 Cov.: 33 AF XY: 0.187 AC XY: 13915 AN XY: 74306

African (AFR) AF: 0.288 AC: 11936 AN: 41450

American (AMR) AF: 0.242 AC: 3687 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 435 AN: 3472

East Asian (EAS) AF: 0.499 AC: 2580 AN: 5170

South Asian (SAS) AF: 0.125 AC: 602 AN: 4818

European-Finnish (FIN) AF: 0.157 AC: 1661 AN: 10554

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.0863 AC: 5869 AN: 67980

Other (OTH) AF: 0.174 AC: 368 AN: 2112

Alfa AF: 0.122 Hom.: 4301

Bravo AF: 0.195

Asia WGS AF: 0.284 AC: 988 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.47
DANN	Benign	0.44
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10420382; hg19: chr19-7134013;