rs4646957

Positions:

• chr10-92470155-C-T

Variant summary

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

The NM_004969.4(IDE):​c.2208+99G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 766,512 control chromosomes in the GnomAD database, including 58,467 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 0.44 (16062 hom., cov: 32)
  • Exomes 𝑓: 0.36 (42405 hom.)
• Consequence: IDE NM_004969.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.306

Genes affected

IDE (HGNC:5381): (insulin degrading enzyme) This gene encodes a zinc metallopeptidase that degrades intracellular insulin, and thereby terminates insulins activity, as well as participating in intercellular peptide signalling by degrading diverse peptides such as glucagon, amylin, bradykinin, and kallidin. The preferential affinity of this enzyme for insulin results in insulin-mediated inhibition of the degradation of other peptides such as beta-amyloid. Deficiencies in this protein's function are associated with Alzheimer's disease and type 2 diabetes mellitus but mutations in this gene have not been shown to be causitive for these diseases. This protein localizes primarily to the cytoplasm but in some cell types localizes to the extracellular space, cell membrane, peroxisome, and mitochondrion. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional transcript variants have been described but have not been experimentally verified.[provided by RefSeq, Sep 2009]

IDE (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.626 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDE	NM_004969.4	c.2208+99G>A		intron_variant		ENST00000265986.11	NP_004960.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDE	ENST00000265986.11	c.2208+99G>A		intron_variant		1	NM_004969.4	ENSP00000265986.6

Frequencies

GnomAD3 genomes AF: 0.440 AC: 66831 AN: 151886 Hom.: 16037 Cov.: 32

Gnomad AFR AF: 0.633

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.464

Gnomad ASJ AF: 0.285

Gnomad EAS AF: 0.249

Gnomad SAS AF: 0.320

Gnomad FIN AF: 0.422

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.356

Gnomad OTH AF: 0.392

GnomAD4 exome AF: 0.364 AC: 223813 AN: 614508 Hom.: 42405 AF XY: 0.360 AC XY: 115429 AN XY: 320222

Gnomad4 AFR exome AF: 0.634

Gnomad4 AMR exome AF: 0.489

Gnomad4 ASJ exome AF: 0.288

Gnomad4 EAS exome AF: 0.275

Gnomad4 SAS exome AF: 0.321

Gnomad4 FIN exome AF: 0.414

Gnomad4 NFE exome AF: 0.357

Gnomad4 OTH exome AF: 0.352

GnomAD4 genome AF: 0.440 AC: 66908 AN: 152004 Hom.: 16062 Cov.: 32 AF XY: 0.441 AC XY: 32763 AN XY: 74302

Gnomad4 AFR AF: 0.632

Gnomad4 AMR AF: 0.464

Gnomad4 ASJ AF: 0.285

Gnomad4 EAS AF: 0.249

Gnomad4 SAS AF: 0.320

Gnomad4 FIN AF: 0.422

Gnomad4 NFE AF: 0.356

Gnomad4 OTH AF: 0.392

Alfa AF: 0.374 Hom.: 10996

Bravo AF: 0.449

Asia WGS AF: 0.334 AC: 1164 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.44
DANN	Benign	0.20

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: rs4646957; hg19: chr10-94229912; COSMIC: COSV56423228; COSMIC: COSV56423228;