rs2421943

Variant names:

• chr10-92552058-G-A
• rs2421943
• NM_004969.4:c.99-14508C>T

Variant summary

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

The NM_004969.4(IDE):​c.99-14508C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 151,996 control chromosomes in the GnomAD database, including 12,001 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 0.37 (12001 hom., cov: 31)
• Consequence: IDE NM_004969.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.123
• Publications: 10 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.652 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDE	NM_004969.4	MANE Select	c.99-14508C>T		intron	N/A	NP_004960.2
	IDE	NM_001322793.2		c.99-14508C>T		intron	N/A	NP_001309722.1
	IDE	NM_001322794.2		c.99-14508C>T		intron	N/A	NP_001309723.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDE	ENST00000265986.11	TSL:1 MANE Select	c.99-14508C>T		intron	N/A	ENSP00000265986.6
	IDE	ENST00000478361.6	TSL:1	n.*308+2664C>T		intron	N/A	ENSP00000473506.1
	IDE	ENST00000971392.1		c.99-14508C>T		intron	N/A	ENSP00000641451.1

Frequencies

GnomAD3 genomes AF: 0.375 AC: 56914 AN: 151878 Hom.: 12003 Cov.: 31

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.547

Gnomad AMR AF: 0.326

Gnomad ASJ AF: 0.568

Gnomad EAS AF: 0.671

Gnomad SAS AF: 0.520

Gnomad FIN AF: 0.441

Gnomad MID AF: 0.439

Gnomad NFE AF: 0.442

Gnomad OTH AF: 0.399

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.375 AC: 56926 AN: 151996 Hom.: 12001 Cov.: 31 AF XY: 0.377 AC XY: 27999 AN XY: 74292

African (AFR) AF: 0.190 AC: 7866 AN: 41464

American (AMR) AF: 0.326 AC: 4976 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.568 AC: 1971 AN: 3472

East Asian (EAS) AF: 0.671 AC: 3474 AN: 5178

South Asian (SAS) AF: 0.520 AC: 2505 AN: 4820

European-Finnish (FIN) AF: 0.441 AC: 4650 AN: 10534

Middle Eastern (MID) AF: 0.425 AC: 124 AN: 292

European-Non Finnish (NFE) AF: 0.442 AC: 30020 AN: 67952

Other (OTH) AF: 0.398 AC: 841 AN: 2112

Alfa AF: 0.408 Hom.: 4677

Bravo AF: 0.361

Asia WGS AF: 0.540 AC: 1875 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.5
DANN	Benign	0.22
PhyloP100		0.12
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: rs2421943; hg19: chr10-94311815;