rs4646955

Variant names:

• chr10-92534534-A-G
• rs4646955
• NM_004969.4:c.491+44T>C

Variant summary

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

The NM_004969.4(IDE):​c.491+44T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,014,588 control chromosomes in the GnomAD database, including 28,699 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 0.20 (3473 hom., cov: 32)
  • Exomes 𝑓: 0.23 (25226 hom.)
• Consequence: IDE NM_004969.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.102
• Publications: 17 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.255 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004969.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDE	NM_004969.4	MANE Select	c.491+44T>C		intron	N/A	NP_004960.2
	IDE	NM_001322793.2		c.491+44T>C		intron	N/A	NP_001309722.1
	IDE	NM_001322794.2		c.491+44T>C		intron	N/A	NP_001309723.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDE	ENST00000265986.11	TSL:1 MANE Select	c.491+44T>C		intron	N/A	ENSP00000265986.6
	IDE	ENST00000478361.6	TSL:1	n.*701+44T>C		intron	N/A	ENSP00000473506.1
	IDE	ENST00000971392.1		c.491+44T>C		intron	N/A	ENSP00000641451.1

Frequencies

GnomAD3 genomes AF: 0.197 AC: 29939 AN: 151986 Hom.: 3474 Cov.: 32

Gnomad AFR AF: 0.0963

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.258

Gnomad EAS AF: 0.0458

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.318

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.258

Gnomad OTH AF: 0.195

GnomAD2 exomes AF: 0.206 AC: 45199 AN: 219692 AF XY: 0.208

Gnomad AFR exome AF: 0.0924

Gnomad AMR exome AF: 0.126

Gnomad ASJ exome AF: 0.272

Gnomad EAS exome AF: 0.0450

Gnomad FIN exome AF: 0.314

Gnomad NFE exome AF: 0.257

Gnomad OTH exome AF: 0.223

GnomAD4 exome AF: 0.229 AC: 197857 AN: 862484 Hom.: 25226 Cov.: 11 AF XY: 0.227 AC XY: 101691 AN XY: 448344

African (AFR) AF: 0.0911 AC: 1891 AN: 20752

American (AMR) AF: 0.131 AC: 4455 AN: 34094

Ashkenazi Jewish (ASJ) AF: 0.260 AC: 5349 AN: 20542

East Asian (EAS) AF: 0.0341 AC: 1249 AN: 36656

South Asian (SAS) AF: 0.139 AC: 9215 AN: 66458

European-Finnish (FIN) AF: 0.301 AC: 15480 AN: 51368

Middle Eastern (MID) AF: 0.220 AC: 972 AN: 4426

European-Non Finnish (NFE) AF: 0.256 AC: 150511 AN: 588240

Other (OTH) AF: 0.219 AC: 8735 AN: 39948

GnomAD4 genome AF: 0.197 AC: 29932 AN: 152104 Hom.: 3473 Cov.: 32 AF XY: 0.198 AC XY: 14741 AN XY: 74346

African (AFR) AF: 0.0962 AC: 3992 AN: 41504

American (AMR) AF: 0.174 AC: 2654 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 895 AN: 3472

East Asian (EAS) AF: 0.0455 AC: 236 AN: 5182

South Asian (SAS) AF: 0.129 AC: 621 AN: 4826

European-Finnish (FIN) AF: 0.318 AC: 3352 AN: 10550

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.258 AC: 17549 AN: 67972

Other (OTH) AF: 0.194 AC: 409 AN: 2110

Alfa AF: 0.230 Hom.: 12053

Bravo AF: 0.181

Asia WGS AF: 0.116 AC: 403 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.68
DANN	Benign	0.61
PhyloP100		0.10
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: rs4646955; hg19: chr10-94294291;