rs10420008

Variant names:

• chr19-7234564-A-G
• rs10420008
• NM_000208.4:c.652+32781T>C

Variant summary

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

The NM_000208.4(INSR):​c.652+32781T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 152,016 control chromosomes in the GnomAD database, including 5,503 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 0.26 (5503 hom., cov: 32)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.231
• Publications: 7 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.585 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.652+32781T>C		intron_variant	Intron 2 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.652+32781T>C		intron_variant	Intron 2 of 20		NP_001073285.1
INSR	XM_011527988.3	c.652+32781T>C		intron_variant	Intron 2 of 21		XP_011526290.2
INSR	XM_011527989.4	c.652+32781T>C		intron_variant	Intron 2 of 20		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.652+32781T>C		intron_variant	Intron 2 of 21	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.652+32781T>C		intron_variant	Intron 2 of 20	1		ENSP00000342838.4
INSR	ENST00000598216.1	n.627+32781T>C		intron_variant	Intron 2 of 9	1

Frequencies

GnomAD3 genomes AF: 0.256 AC: 38828 AN: 151898 Hom.: 5488 Cov.: 32

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.363

Gnomad ASJ AF: 0.186

Gnomad EAS AF: 0.602

Gnomad SAS AF: 0.257

Gnomad FIN AF: 0.278

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.243

Gnomad OTH AF: 0.249

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

GnomAD4 genome AF: 0.256 AC: 38860 AN: 152016 Hom.: 5503 Cov.: 32 AF XY: 0.259 AC XY: 19246 AN XY: 74300

African (AFR) AF: 0.196 AC: 8148 AN: 41472

American (AMR) AF: 0.364 AC: 5553 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 644 AN: 3470

East Asian (EAS) AF: 0.603 AC: 3110 AN: 5160

South Asian (SAS) AF: 0.257 AC: 1238 AN: 4816

European-Finnish (FIN) AF: 0.278 AC: 2941 AN: 10584

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.243 AC: 16521 AN: 67966

Other (OTH) AF: 0.246 AC: 519 AN: 2108

Alfa AF: 0.249 Hom.: 20617

Bravo AF: 0.260

Asia WGS AF: 0.346 AC: 1202 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.3
DANN	Benign	0.67
PhyloP100		0.23
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: rs10420008; hg19: chr19-7234575;