rs10417205

Variant names:

• chr19-7254696-T-A
• rs10417205
• NM_000208.4:c.652+12649A>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.652+12649A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.68 in 152,070 control chromosomes in the GnomAD database, including 35,379 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 0.68 (35379 hom., cov: 32)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.170
• Publications: 5 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.755 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.652+12649A>T		intron_variant	Intron 2 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.652+12649A>T		intron_variant	Intron 2 of 20		NP_001073285.1
INSR	XM_011527988.3	c.652+12649A>T		intron_variant	Intron 2 of 21		XP_011526290.2
INSR	XM_011527989.4	c.652+12649A>T		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+12649A>T		intron_variant	Intron 2 of 21	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.652+12649A>T		intron_variant	Intron 2 of 20	1		ENSP00000342838.4
INSR	ENST00000598216.1	n.627+12649A>T		intron_variant	Intron 2 of 9	1

Frequencies

GnomAD3 genomes AF: 0.680 AC: 103345 AN: 151950 Hom.: 35342 Cov.: 32

Gnomad AFR AF: 0.652

Gnomad AMI AF: 0.782

Gnomad AMR AF: 0.767

Gnomad ASJ AF: 0.658

Gnomad EAS AF: 0.668

Gnomad SAS AF: 0.608

Gnomad FIN AF: 0.718

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.678

Gnomad OTH AF: 0.675

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

GnomAD4 genome AF: 0.680 AC: 103428 AN: 152070 Hom.: 35379 Cov.: 32 AF XY: 0.682 AC XY: 50705 AN XY: 74340

African (AFR) AF: 0.652 AC: 27032 AN: 41468

American (AMR) AF: 0.767 AC: 11702 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.658 AC: 2282 AN: 3470

East Asian (EAS) AF: 0.668 AC: 3459 AN: 5176

South Asian (SAS) AF: 0.609 AC: 2932 AN: 4816

European-Finnish (FIN) AF: 0.718 AC: 7605 AN: 10594

Middle Eastern (MID) AF: 0.650 AC: 191 AN: 294

European-Non Finnish (NFE) AF: 0.678 AC: 46101 AN: 67966

Other (OTH) AF: 0.667 AC: 1411 AN: 2114

Alfa AF: 0.679 Hom.: 4366

Bravo AF: 0.685

Asia WGS AF: 0.641 AC: 2228 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.5
DANN	Benign	0.45
PhyloP100		-0.17
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: rs10417205; hg19: chr19-7254707;