10-92468974-A-G

Variant names:

• chr10-92468974-A-G
• rs114285269
• NM_004969.4:c.2225T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004969.4(IDE):​c.2225T>C​(p.Met742Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000577 in 1,595,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: IDE NM_004969.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.84
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.038588613).

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.2225T>C	p.Met742Thr	missense	Exon 19 of 25	NP_004960.2	P14735-1
	IDE	NM_001322793.2		c.2225T>C	p.Met742Thr	missense	Exon 19 of 25	NP_001309722.1	A0A3B3ISG5
	IDE	NM_001322794.2		c.2108T>C	p.Met703Thr	missense	Exon 19 of 25	NP_001309723.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDE	ENST00000265986.11	TSL:1 MANE Select	c.2225T>C	p.Met742Thr	missense	Exon 19 of 25	ENSP00000265986.6	P14735-1
	IDE	ENST00000971392.1		c.2366T>C	p.Met789Thr	missense	Exon 20 of 26	ENSP00000641451.1
	IDE	ENST00000857320.1		c.2225T>C	p.Met742Thr	missense	Exon 19 of 26	ENSP00000527379.1

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000956 AC: 24 AN: 251094 AF XY: 0.0000663

Gnomad AFR exome AF: 0.00141

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000333 AC: 48 AN: 1443086 Hom.: 0 Cov.: 26 AF XY: 0.0000292 AC XY: 21 AN XY: 719364

African (AFR) AF: 0.00124 AC: 41 AN: 33116

American (AMR) AF: 0.0000224 AC: 1 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26038

East Asian (EAS) AF: 0.00 AC: 0 AN: 39590

South Asian (SAS) AF: 0.00 AC: 0 AN: 85888

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00000548 AC: 6 AN: 1094882

Other (OTH) AF: 0.00 AC: 0 AN: 59784

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74496

African (AFR) AF: 0.00106 AC: 44 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000163 Hom.: 0

Bravo AF: 0.000374

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000115 AC: 14

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	22
DANN	Benign	0.88
DEOGEN2	Benign	0.082	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.052
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.47	N
PhyloP100		6.8
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.27
Sift	Benign	0.29	T
Sift4G	Benign	0.22	T
Polyphen		0.010	B
Vest4		0.60
MVP		0.22
MPC		0.37
ClinPred		0.17	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.62
Mutation Taster		=35/65	disease causing

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: rs114285269; hg19: chr10-94228731;