19-7205229-C-T

Position:

• chr19-7205229-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000208.4(INSR):​c.653-20592G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 152,208 control chromosomes in the GnomAD database, including 2,893 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 0.18 (2893 hom., cov: 33)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.644

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]

ACMG classification

Verdict is Benign. Variant got -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 = 0.225 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INSR	NM_000208.4	c.653-20592G>A		intron_variant		ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.653-20592G>A		intron_variant			NP_001073285.1
INSR	XM_011527988.3	c.653-20592G>A		intron_variant			XP_011526290.2
INSR	XM_011527989.4	c.653-20592G>A		intron_variant			XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.653-20592G>A		intron_variant		1	NM_000208.4	ENSP00000303830	A2
INSR	ENST00000341500.9	c.653-20592G>A		intron_variant		1		ENSP00000342838	P3
INSR	ENST00000598216.1	n.628-20592G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.184 AC: 28016 AN: 152090 Hom.: 2891 Cov.: 33

Gnomad AFR AF: 0.0918

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.218

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.0770

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.199

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

GnomAD4 genome AF: 0.184 AC: 28031 AN: 152208 Hom.: 2893 Cov.: 33 AF XY: 0.185 AC XY: 13768 AN XY: 74412

Gnomad4 AFR AF: 0.0919

Gnomad4 AMR AF: 0.218

Gnomad4 ASJ AF: 0.221

Gnomad4 EAS AF: 0.0771

Gnomad4 SAS AF: 0.196

Gnomad4 FIN AF: 0.249

Gnomad4 NFE AF: 0.228

Gnomad4 OTH AF: 0.199

Alfa AF: 0.222 Hom.: 8024

Bravo AF: 0.179

Asia WGS AF: 0.159 AC: 554 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	12
DANN	Benign	0.85

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

Publications

LitVar

Other links and lift over

dbSNP: rs10426094; hg19: chr19-7205240;