dbSNP rs4646958: IDE:c.2965-63A>T (chr10-92454602-T-A) – 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.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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.884

Publications

7 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:

Genome browser will be placed here

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=-0.81).

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 rank	MANE	Protein	UniProt
IDE	NM_004969.4 link	c.2965-63A>T		intron_variant	Intron 24 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.2965-63A>T		intron_variant	Intron 24 of 24	1	NM_004969.4	ENSP00000265986.6		P14735-1

Frequencies

GnomAD3 genomes

AF:

0.0978

AC:

14884

AN:

152154

Hom.:

838

Cov.:

show subpopulations

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

show subpopulations

African (AFR)

AF:

0.0928

AC:

2424

AN:

26124

American (AMR)

AF:

0.229

AC:

9706

AN:

42352

Ashkenazi Jewish (ASJ)

AF:

0.0520

AC:

1225

AN:

23558

East Asian (EAS)

AF:

0.180

AC:

6770

AN:

37608

South Asian (SAS)

AF:

0.175

AC:

13550

AN:

77494

European-Finnish (FIN)

AF:

0.0656

AC:

3410

AN:

51966

Middle Eastern (MID)

AF:

0.0746

AC:

273

AN:

3658

European-Non Finnish (NFE)

AF:

0.0902

AC:

69627

AN:

771972

Other (OTH)

AF:

0.0889

AC:

4227

AN:

47524

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

4752

9505

14257

19010

23762

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2262

4524

6786

9048

11310

<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:

0.0979

AC:

14907

AN:

152272

Hom.:

840

Cov.:

AF XY:

0.0990

AC XY:

7369

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0918

AC:

3814

AN:

41564

American (AMR)

AF:

0.152

AC:

2318

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0524

AC:

182

AN:

3472

East Asian (EAS)

AF:

0.141

AC:

729

AN:

5178

South Asian (SAS)

AF:

0.172

AC:

830

AN:

4830

European-Finnish (FIN)

AF:

0.0530

AC:

563

AN:

10614

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0920

AC:

6254

AN:

68012

Other (OTH)

AF:

0.0899

AC:

190

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

718

1436

2154

2872

3590

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

344

516

688

860

<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:

0.0996

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

(source)

DANN

Benign

0.74

PhyloP100

-0.88

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