rs10401628

Variant names:

• chr19-7126207-A-G
• rs10401628
• NM_000208.4:c.3013+377T>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.3013+377T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.908 in 152,162 control chromosomes in the GnomAD database, including 62,801 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 0.91 (62801 hom., cov: 31)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.81
• Publications: 6 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 = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.3013+377T>C		intron_variant	Intron 16 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.2977+377T>C		intron_variant	Intron 15 of 20		NP_001073285.1
INSR	XM_011527988.3	c.3010+377T>C		intron_variant	Intron 16 of 21		XP_011526290.2
INSR	XM_011527989.4	c.2974+377T>C		intron_variant	Intron 15 of 20		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.3013+377T>C		intron_variant	Intron 16 of 21	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.2977+377T>C		intron_variant	Intron 15 of 20	1		ENSP00000342838.4

Frequencies

GnomAD3 genomes AF: 0.908 AC: 138096 AN: 152044 Hom.: 62751 Cov.: 31

Gnomad AFR AF: 0.939

Gnomad AMI AF: 0.823

Gnomad AMR AF: 0.928

Gnomad ASJ AF: 0.926

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.937

Gnomad FIN AF: 0.862

Gnomad MID AF: 0.946

Gnomad NFE AF: 0.883

Gnomad OTH AF: 0.916

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

GnomAD4 genome AF: 0.908 AC: 138204 AN: 152162 Hom.: 62801 Cov.: 31 AF XY: 0.908 AC XY: 67538 AN XY: 74382

African (AFR) AF: 0.939 AC: 39008 AN: 41534

American (AMR) AF: 0.928 AC: 14182 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.926 AC: 3215 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5167 AN: 5170

South Asian (SAS) AF: 0.936 AC: 4510 AN: 4816

European-Finnish (FIN) AF: 0.862 AC: 9108 AN: 10570

Middle Eastern (MID) AF: 0.939 AC: 276 AN: 294

European-Non Finnish (NFE) AF: 0.883 AC: 60050 AN: 67998

Other (OTH) AF: 0.917 AC: 1937 AN: 2112

Alfa AF: 0.894 Hom.: 42234

Bravo AF: 0.914

Asia WGS AF: 0.962 AC: 3345 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	0.24
DANN	Benign	0.74
PhyloP100		-1.8
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: rs10401628; hg19: chr19-7126218;