rs10500204

Variant names:

• chr19-7182952-A-C
• rs10500204
• NM_000208.4:c.974+1364T>G

Your query was ambiguous. Multiple possible variants found:

• chr19-7182952-A-C
• chr19-7182952-A-T

Variant summary

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

The NM_000208.4(INSR):​c.974+1364T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 149,958 control chromosomes in the GnomAD database, including 4,905 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 0.25 (4905 hom., cov: 28)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0760
• Publications: 17 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=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.268 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	NM_000208.4	MANE Select	c.974+1364T>G		intron	N/A	NP_000199.2
	INSR	NM_001079817.3		c.974+1364T>G		intron	N/A	NP_001073285.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	ENST00000302850.10	TSL:1 MANE Select	c.974+1364T>G		intron	N/A	ENSP00000303830.4
	INSR	ENST00000341500.9	TSL:1	c.974+1364T>G		intron	N/A	ENSP00000342838.4
	INSR	ENST00000598216.1	TSL:1	n.949+1364T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.252 AC: 37838 AN: 149856 Hom.: 4905 Cov.: 28

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.269

Gnomad ASJ AF: 0.415

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.262

Gnomad FIN AF: 0.295

Gnomad MID AF: 0.283

Gnomad NFE AF: 0.271

Gnomad OTH AF: 0.298

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

GnomAD4 genome AF: 0.252 AC: 37844 AN: 149958 Hom.: 4905 Cov.: 28 AF XY: 0.252 AC XY: 18355 AN XY: 72866

African (AFR) AF: 0.202 AC: 8308 AN: 41072

American (AMR) AF: 0.268 AC: 4008 AN: 14932

Ashkenazi Jewish (ASJ) AF: 0.415 AC: 1435 AN: 3456

East Asian (EAS) AF: 0.144 AC: 737 AN: 5118

South Asian (SAS) AF: 0.262 AC: 1249 AN: 4770

European-Finnish (FIN) AF: 0.295 AC: 2844 AN: 9632

Middle Eastern (MID) AF: 0.284 AC: 83 AN: 292

European-Non Finnish (NFE) AF: 0.271 AC: 18354 AN: 67700

Other (OTH) AF: 0.297 AC: 617 AN: 2080

Alfa AF: 0.272 Hom.: 9074

Bravo AF: 0.251

Asia WGS AF: 0.205 AC: 712 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	12
DANN	Benign	0.75
PhyloP100		0.076
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: rs10500204; hg19: chr19-7182963;