NM_004969.4:c.2761+864G>A

Variant names:

• chr10-92462867-C-T
• rs551266
• NM_004969.4:c.2761+864G>A

Variant summary

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

The NM_004969.4(IDE):​c.2761+864G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.85 in 152,234 control chromosomes in the GnomAD database, including 55,232 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 0.85 (55232 hom., cov: 32)
• Consequence: IDE NM_004969.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.565
• Publications: 5 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=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.912 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.2761+864G>A		intron	N/A	NP_004960.2
	IDE	NM_001322793.2		c.2761+864G>A		intron	N/A	NP_001309722.1
	IDE	NM_001322794.2		c.2644+864G>A		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.2761+864G>A		intron	N/A	ENSP00000265986.6
	IDE	ENST00000650060.2		c.2761+864G>A		intron	N/A	ENSP00000497272.1
	IDE	ENST00000676540.1		c.2839+864G>A		intron	N/A	ENSP00000504633.1

Frequencies

GnomAD3 genomes AF: 0.850 AC: 129311 AN: 152116 Hom.: 55187 Cov.: 32

Gnomad AFR AF: 0.919

Gnomad AMI AF: 0.876

Gnomad AMR AF: 0.815

Gnomad ASJ AF: 0.878

Gnomad EAS AF: 0.923

Gnomad SAS AF: 0.839

Gnomad FIN AF: 0.862

Gnomad MID AF: 0.769

Gnomad NFE AF: 0.809

Gnomad OTH AF: 0.826

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

GnomAD4 genome AF: 0.850 AC: 129414 AN: 152234 Hom.: 55232 Cov.: 32 AF XY: 0.850 AC XY: 63296 AN XY: 74432

African (AFR) AF: 0.919 AC: 38191 AN: 41540

American (AMR) AF: 0.815 AC: 12460 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.878 AC: 3047 AN: 3472

East Asian (EAS) AF: 0.923 AC: 4777 AN: 5178

South Asian (SAS) AF: 0.838 AC: 4045 AN: 4826

European-Finnish (FIN) AF: 0.862 AC: 9138 AN: 10606

Middle Eastern (MID) AF: 0.759 AC: 223 AN: 294

European-Non Finnish (NFE) AF: 0.809 AC: 54998 AN: 68004

Other (OTH) AF: 0.824 AC: 1741 AN: 2112

Alfa AF: 0.820 Hom.: 191329

Bravo AF: 0.851

Asia WGS AF: 0.875 AC: 3041 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	0.23
DANN	Benign	0.49
PhyloP100		-0.56
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: rs551266; hg19: chr10-94222624;