rs4646958

Positions:

• chr10-92454602-T-A

Variant summary

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

The NM_004969.4(IDE):​c.2965-63A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,234,528 control chromosomes in the GnomAD database, including 7,521 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 0.098 (840 hom., cov: 33)
  • Exomes 𝑓: 0.10 (6681 hom.)
• Consequence: IDE NM_004969.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.884

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDE	NM_004969.4	c.2965-63A>T		intron_variant		ENST00000265986.11	NP_004960.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDE	ENST00000265986.11	c.2965-63A>T		intron_variant		1	NM_004969.4	ENSP00000265986	P1

Frequencies

GnomAD3 genomes AF: 0.0978 AC: 14884 AN: 152154 Hom.: 838 Cov.: 33

Gnomad AFR AF: 0.0919

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.0524

Gnomad EAS AF: 0.140

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.0530

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0919

Gnomad OTH AF: 0.0880

GnomAD4 exome AF: 0.103 AC: 111212 AN: 1082256 Hom.: 6681 AF XY: 0.105 AC XY: 58246 AN XY: 553854

Gnomad4 AFR exome AF: 0.0928

Gnomad4 AMR exome AF: 0.229

Gnomad4 ASJ exome AF: 0.0520

Gnomad4 EAS exome AF: 0.180

Gnomad4 SAS exome AF: 0.175

Gnomad4 FIN exome AF: 0.0656

Gnomad4 NFE exome AF: 0.0902

Gnomad4 OTH exome AF: 0.0889

GnomAD4 genome AF: 0.0979 AC: 14907 AN: 152272 Hom.: 840 Cov.: 33 AF XY: 0.0990 AC XY: 7369 AN XY: 74448

Gnomad4 AFR AF: 0.0918

Gnomad4 AMR AF: 0.152

Gnomad4 ASJ AF: 0.0524

Gnomad4 EAS AF: 0.141

Gnomad4 SAS AF: 0.172

Gnomad4 FIN AF: 0.0530

Gnomad4 NFE AF: 0.0920

Gnomad4 OTH AF: 0.0899

Alfa AF: 0.0996 Hom.: 100

Bravo AF: 0.104

Asia WGS AF: 0.134 AC: 465 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.079
DANN	Benign	0.74

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: rs4646958; hg19: chr10-94214359;