Genetic Variant IDE:c.*2897G>A (chr10-92451547-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004969.4(IDE):c.*2897G>A variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.782 in 152,738 control chromosomes in the GnomAD database, including 47,239 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 0.78 ( 47089 hom., cov: 31)

Exomes 𝑓: 0.68 ( 150 hom. )

Consequence

IDE
NM_004969.4 downstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.772

Publications

12 publications found

Variant links:

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 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.97).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.899 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IDE	NM_004969.4	MANE Select	c.*2897G>A	downstream_gene	N/A	NP_004960.2	P14735-1
IDE	NM_001322793.2		c.*2897G>A	downstream_gene	N/A	NP_001309722.1	A0A3B3ISG5
IDE	NM_001322794.2		c.*2897G>A	downstream_gene	N/A	NP_001309723.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IDE	ENST00000265986.11	TSL:1 MANE Select	c.*2897G>A	downstream_gene	N/A	ENSP00000265986.6	P14735-1
IDE	ENST00000650060.2		c.*2897G>A	downstream_gene	N/A	ENSP00000497272.1	A0A3B3ISG5
IDE	ENST00000371581.9	TSL:2	c.*2897G>A	downstream_gene	N/A	ENSP00000360637.5	P14735-2

Frequencies

GnomAD3 genomes

AF:

0.782

AC:

118885

AN:

151998

Hom.:

47043

Cov.:

show subpopulations

Gnomad AFR

AF:

0.889

Gnomad AMI

AF:

0.806

Gnomad AMR

AF:

0.747

Gnomad ASJ

AF:

0.688

Gnomad EAS

AF:

0.921

Gnomad SAS

AF:

0.817

Gnomad FIN

AF:

0.812

Gnomad MID

AF:

0.646

Gnomad NFE

AF:

0.713

Gnomad OTH

AF:

0.751

GnomAD4 exome

AF:

0.682

AC:

424

AN:

622

Hom.:

150

AF XY:

0.688

AC XY:

234

AN XY:

340

show subpopulations

African (AFR)

AF:

0.714

AC:

AN:

American (AMR)

AF:

0.500

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

AN:

East Asian (EAS)

AF:

0.871

AC:

AN:

South Asian (SAS)

AF:

0.500

AC:

AN:

European-Finnish (FIN)

AF:

0.839

AC:

AN:

Middle Eastern (MID)

AF:

1.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.643

AC:

293

AN:

456

Other (OTH)

AF:

0.550

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.782

AC:

118987

AN:

152116

Hom.:

47089

Cov.:

AF XY:

0.786

AC XY:

58444

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.889

AC:

36922

AN:

41522

American (AMR)

AF:

0.748

AC:

11431

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.688

AC:

2389

AN:

3472

East Asian (EAS)

AF:

0.921

AC:

4762

AN:

5170

South Asian (SAS)

AF:

0.817

AC:

3933

AN:

4816

European-Finnish (FIN)

AF:

0.812

AC:

8602

AN:

10598

Middle Eastern (MID)

AF:

0.643

AC:

189

AN:

294

European-Non Finnish (NFE)

AF:

0.713

AC:

48440

AN:

67934

Other (OTH)

AF:

0.750

AC:

1584

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1278

2557

3835

5114

6392

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

868

1736

2604

3472

4340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.734

Hom.:

10625

Bravo

AF:

0.782

Asia WGS

AF:

0.859

AC:

2988

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.14

(source)

DANN

Benign

0.33

PhyloP100

-0.77

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over