Genetic Variant NM_004969.4:c.1740-193_1740-190delACAC (chr10-92479610-AGTGT-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004969.4(IDE):c.1740-193_1740-190delACAC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00433 in 462,888 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0062 ( 1 hom. )

Consequence

IDE
NM_004969.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.478

Publications

1 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Variant has high frequency in the EAS (0.0144) population. However there is too low homozygotes in high coverage region: (expected more than 2, got 1).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDE	NM_004969.4 link	c.1740-193_1740-190delACAC		intron_variant	Intron 14 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.1740-193_1740-190delACAC		intron_variant	Intron 14 of 24	1	NM_004969.4	ENSP00000265986.6		P14735-1

Frequencies

GnomAD3 genomes

AF:

0.000480

AC:

AN:

150150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000586

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000332

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.000629

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000534

Gnomad OTH

AF:

0.00146

GnomAD4 exome

AF:

0.00617

AC:

1930

AN:

312738

Hom.:

AF XY:

0.00621

AC XY:

1016

AN XY:

163544

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00151

AC:

AN:

9926

American (AMR)

AF:

0.00424

AC:

AN:

14148

Ashkenazi Jewish (ASJ)

AF:

0.00521

AC:

AN:

9986

East Asian (EAS)

AF:

0.0158

AC:

334

AN:

21158

South Asian (SAS)

AF:

0.00907

AC:

236

AN:

26008

European-Finnish (FIN)

AF:

0.00639

AC:

136

AN:

21270

Middle Eastern (MID)

AF:

0.00434

AC:

AN:

1382

European-Non Finnish (NFE)

AF:

0.00519

AC:

988

AN:

190226

Other (OTH)

AF:

0.00553

AC:

103

AN:

18634

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.270

Heterozygous variant carriers

229

459

688

918

1147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000480

AC:

AN:

150150

Hom.:

Cov.:

AF XY:

0.000382

AC XY:

AN XY:

73222

show subpopulations

African (AFR)

AF:

0.000586

AC:

AN:

40962

American (AMR)

AF:

0.000332

AC:

AN:

15042

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3410

East Asian (EAS)

AF:

0.000194

AC:

AN:

5158

South Asian (SAS)

AF:

0.000629

AC:

AN:

4766

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10148

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.000534

AC:

AN:

67388

Other (OTH)

AF:

0.00146

AC:

AN:

2058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Alfa

AF:

0.00

Hom.:

211

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.48

Mutation Taster

=100/0

polymorphism

(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