NM_004969.4:c.-51C>G

Variant names:

• chr10-92574070-G-C
• rs4646954
• NM_004969.4:c.-51C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004969.4(IDE):​c.-51C>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000395 in 1,266,954 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000039 (0 hom.)
• Consequence: IDE NM_004969.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.70
• Publications: 20 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]

KIF11 (HGNC:6388): (kinesin family member 11) This gene encodes a motor protein that belongs to the kinesin-like protein family. Members of this protein family are known to be involved in various kinds of spindle dynamics. The function of this gene product includes chromosome positioning, centrosome separation and establishing a bipolar spindle during cell mitosis. [provided by RefSeq, Jul 2008]

KIF11 Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).

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.-51C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 25	NP_004960.2
	IDE	NM_004969.4	MANE Select	c.-51C>G		5_prime_UTR	Exon 1 of 25	NP_004960.2
	IDE	NM_001322793.2		c.-51C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 25	NP_001309722.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDE	ENST00000265986.11	TSL:1 MANE Select	c.-51C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 25	ENSP00000265986.6
	IDE	ENST00000265986.11	TSL:1 MANE Select	c.-51C>G		5_prime_UTR	Exon 1 of 25	ENSP00000265986.6
	IDE	ENST00000650060.2		c.-51C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 25	ENSP00000497272.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000395 AC: 5 AN: 1266954 Hom.: 0 Cov.: 19 AF XY: 0.00000477 AC XY: 3 AN XY: 628678

African (AFR) AF: 0.00 AC: 0 AN: 25892

American (AMR) AF: 0.0000374 AC: 1 AN: 26726

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23212

East Asian (EAS) AF: 0.00 AC: 0 AN: 30528

South Asian (SAS) AF: 0.00 AC: 0 AN: 72166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4194

European-Non Finnish (NFE) AF: 0.00000403 AC: 4 AN: 993356

Other (OTH) AF: 0.00 AC: 0 AN: 53570

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 955

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	19
DANN	Benign	0.93
PhyloP100		3.7
PromoterAI		0.092	Neutral

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: rs4646954; hg19: chr10-94333827;