rs4646958

Variant names:

• chr10-92454602-T-A
• rs4646958
• NM_004969.4:c.2965-63A>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.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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.884
• Publications: 7 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=-0.81).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.162 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDE	NM_004969.4	MANE Select	c.2965-63A>T		intron	N/A	NP_004960.2	P14735-1
	IDE	NM_001322793.2		c.2965-63A>T		intron	N/A	NP_001309722.1	A0A3B3ISG5
	IDE	NM_001322794.2		c.2848-63A>T		intron	N/A	NP_001309723.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDE	ENST00000265986.11	TSL:1 MANE Select	c.2965-63A>T		intron	N/A	ENSP00000265986.6	P14735-1
	IDE	ENST00000971392.1		c.3106-63A>T		intron	N/A	ENSP00000641451.1
	IDE	ENST00000857320.1		c.3070-63A>T		intron	N/A	ENSP00000527379.1

Frequencies

GnomAD3 genomes AF: 0.0978 AC: 14884 AN: 152154 Hom.: 838 Cov.: 33

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

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

GnomAD4 genome AF: 0.0979 AC: 14907 AN: 152272 Hom.: 840 Cov.: 33 AF XY: 0.0990 AC XY: 7369 AN XY: 74448

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: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0920 AC: 6254 AN: 68012

Other (OTH) AF: 0.0899 AC: 190 AN: 2114

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.079
DANN	Benign	0.74
PhyloP100		-0.88
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: rs4646958; hg19: chr10-94214359;