19-7134391-T-G

Variant names:

• chr19-7134391-T-G
• rs6510949
• NM_000208.4:c.2683-2074A>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.2683-2074A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.946 in 152,126 control chromosomes in the GnomAD database, including 68,062 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 0.95 (68062 hom., cov: 31)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.296
• Publications: 8 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=-1.0).
• 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.2683-2074A>C		intron_variant	Intron 13 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.2647-2074A>C		intron_variant	Intron 12 of 20		NP_001073285.1
INSR	XM_011527988.3	c.2683-2074A>C		intron_variant	Intron 13 of 21		XP_011526290.2
INSR	XM_011527989.4	c.2647-2074A>C		intron_variant	Intron 12 of 20		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.2683-2074A>C		intron_variant	Intron 13 of 21	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.2647-2074A>C		intron_variant	Intron 12 of 20	1		ENSP00000342838.4

Frequencies

GnomAD3 genomes AF: 0.946 AC: 143769 AN: 152008 Hom.: 68006 Cov.: 31

Gnomad AFR AF: 0.974

Gnomad AMI AF: 0.980

Gnomad AMR AF: 0.949

Gnomad ASJ AF: 0.909

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.911

Gnomad FIN AF: 0.944

Gnomad MID AF: 0.934

Gnomad NFE AF: 0.929

Gnomad OTH AF: 0.939

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

GnomAD4 genome AF: 0.946 AC: 143884 AN: 152126 Hom.: 68062 Cov.: 31 AF XY: 0.946 AC XY: 70324 AN XY: 74328

African (AFR) AF: 0.974 AC: 40418 AN: 41512

American (AMR) AF: 0.949 AC: 14492 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.909 AC: 3157 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5169 AN: 5172

South Asian (SAS) AF: 0.911 AC: 4389 AN: 4816

European-Finnish (FIN) AF: 0.944 AC: 9949 AN: 10544

Middle Eastern (MID) AF: 0.935 AC: 275 AN: 294

European-Non Finnish (NFE) AF: 0.929 AC: 63158 AN: 68016

Other (OTH) AF: 0.939 AC: 1985 AN: 2114

Alfa AF: 0.930 Hom.: 104170

Bravo AF: 0.949

Asia WGS AF: 0.960 AC: 3339 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	4.1
DANN	Benign	0.37
PhyloP100		0.30
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: rs6510949; hg19: chr19-7134402;