chr19-7145620-G-C

Variant names:

• chr19-7145620-G-C
• rs12461909
• NM_000208.4:c.2268-2530C>G

Variant summary

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

The NM_000208.4(INSR):​c.2268-2530C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0444 in 152,280 control chromosomes in the GnomAD database, including 907 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 0.044 (907 hom., cov: 33)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0820
• Publications: 1 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=-0.73).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.483 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.2268-2530C>G		intron_variant	Intron 11 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.2232-2530C>G		intron_variant	Intron 10 of 20		NP_001073285.1
INSR	XM_011527988.3	c.2268-2530C>G		intron_variant	Intron 11 of 21		XP_011526290.2
INSR	XM_011527989.4	c.2232-2530C>G		intron_variant	Intron 10 of 20		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.2268-2530C>G		intron_variant	Intron 11 of 21	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.2232-2530C>G		intron_variant	Intron 10 of 20	1		ENSP00000342838.4

Frequencies

GnomAD3 genomes AF: 0.0443 AC: 6743 AN: 152164 Hom.: 903 Cov.: 33

Gnomad AFR AF: 0.00827

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.498

Gnomad SAS AF: 0.0591

Gnomad FIN AF: 0.0608

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00390

Gnomad OTH AF: 0.0334

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

GnomAD4 genome AF: 0.0444 AC: 6759 AN: 152280 Hom.: 907 Cov.: 33 AF XY: 0.0525 AC XY: 3912 AN XY: 74450

African (AFR) AF: 0.00835 AC: 347 AN: 41572

American (AMR) AF: 0.167 AC: 2548 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3470

East Asian (EAS) AF: 0.499 AC: 2585 AN: 5180

South Asian (SAS) AF: 0.0585 AC: 282 AN: 4820

European-Finnish (FIN) AF: 0.0608 AC: 645 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00390 AC: 265 AN: 68024

Other (OTH) AF: 0.0336 AC: 71 AN: 2116

Alfa AF: 0.0200 Hom.: 33

Bravo AF: 0.0537

Asia WGS AF: 0.234 AC: 810 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	8.7
DANN	Benign	0.81
PhyloP100		0.082
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: rs12461909; hg19: chr19-7145631;