dbSNP rs4646957: IDE:c.2208+99G>A (chr10-92470155-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.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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.306

Publications

25 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=-0.94).

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 rank	MANE	Protein	UniProt
IDE	NM_004969.4 link	c.2208+99G>A		intron_variant	Intron 18 of 24	ENST00000265986.11	NP_004960.2	P14735-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDE	ENST00000265986.11 link	c.2208+99G>A		intron_variant	Intron 18 of 24	1	NM_004969.4	ENSP00000265986.6		P14735-1

Frequencies

GnomAD3 genomes

AF:

0.440

AC:

66831

AN:

151886

Hom.:

16037

Cov.:

show subpopulations

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

show subpopulations

African (AFR)

AF:

0.634

AC:

9664

AN:

15240

American (AMR)

AF:

0.489

AC:

11058

AN:

22592

Ashkenazi Jewish (ASJ)

AF:

0.288

AC:

4235

AN:

14716

East Asian (EAS)

AF:

0.275

AC:

8596

AN:

31260

South Asian (SAS)

AF:

0.321

AC:

14180

AN:

44152

European-Finnish (FIN)

AF:

0.414

AC:

19155

AN:

46310

Middle Eastern (MID)

AF:

0.286

AC:

1073

AN:

3748

European-Non Finnish (NFE)

AF:

0.357

AC:

145165

AN:

406136

Other (OTH)

AF:

0.352

AC:

10687

AN:

30354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

6685

13370

20054

26739

33424

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2962

5924

8886

11848

14810

<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:

0.440

AC:

66908

AN:

152004

Hom.:

16062

Cov.:

AF XY:

0.441

AC XY:

32763

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.632

AC:

26218

AN:

41452

American (AMR)

AF:

0.464

AC:

7084

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.285

AC:

988

AN:

3472

East Asian (EAS)

AF:

0.249

AC:

1289

AN:

5180

South Asian (SAS)

AF:

0.320

AC:

1540

AN:

4818

European-Finnish (FIN)

AF:

0.422

AC:

4444

AN:

10540

Middle Eastern (MID)

AF:

0.306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.356

AC:

24175

AN:

67960

Other (OTH)

AF:

0.392

AC:

827

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1811

3621

5432

7242

9053

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

598

1196

1794

2392

2990

<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:

0.401

Hom.:

22661

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

(source)

DANN

Benign

0.20

PhyloP100

-0.31

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over