10-92574198-A-G

Variant names:

• chr10-92574198-A-G
• rs4646953
• ENST00000676757.1:c.-131+5A>G

Variant summary

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

The ENST00000676757.1(KIF11):​c.-131+5A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 550,568 control chromosomes in the GnomAD database, including 10,220 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 0.17 (2434 hom., cov: 33)
  • Exomes 𝑓: 0.19 (7786 hom.)
• Consequence: KIF11 ENST00000676757.1 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.63
• Publications: 22 publications found

Genes affected

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]

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=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDE	NM_004969.4	c.-179T>C		upstream_gene_variant		ENST00000265986.11	NP_004960.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDE	ENST00000265986.11	c.-179T>C		upstream_gene_variant		1	NM_004969.4	ENSP00000265986.6

Frequencies

GnomAD3 genomes AF: 0.165 AC: 25124 AN: 152020 Hom.: 2434 Cov.: 33

Gnomad AFR AF: 0.0885

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.0460

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.277

Gnomad MID AF: 0.201

Gnomad NFE AF: 0.208

Gnomad OTH AF: 0.170

GnomAD4 exome AF: 0.187 AC: 74490 AN: 398430 Hom.: 7786 AF XY: 0.184 AC XY: 38573 AN XY: 209426

African (AFR) AF: 0.0882 AC: 712 AN: 8072

American (AMR) AF: 0.128 AC: 1099 AN: 8570

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 2738 AN: 13198

East Asian (EAS) AF: 0.0293 AC: 686 AN: 23448

South Asian (SAS) AF: 0.127 AC: 4530 AN: 35694

European-Finnish (FIN) AF: 0.255 AC: 7599 AN: 29792

Middle Eastern (MID) AF: 0.156 AC: 301 AN: 1934

European-Non Finnish (NFE) AF: 0.207 AC: 52461 AN: 253838

Other (OTH) AF: 0.183 AC: 4364 AN: 23884

GnomAD4 genome AF: 0.165 AC: 25120 AN: 152138 Hom.: 2434 Cov.: 33 AF XY: 0.167 AC XY: 12454 AN XY: 74374

African (AFR) AF: 0.0884 AC: 3672 AN: 41550

American (AMR) AF: 0.155 AC: 2366 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 697 AN: 3466

East Asian (EAS) AF: 0.0457 AC: 235 AN: 5144

South Asian (SAS) AF: 0.119 AC: 571 AN: 4816

European-Finnish (FIN) AF: 0.277 AC: 2935 AN: 10586

Middle Eastern (MID) AF: 0.205 AC: 60 AN: 292

European-Non Finnish (NFE) AF: 0.208 AC: 14113 AN: 67962

Other (OTH) AF: 0.169 AC: 356 AN: 2112

Alfa AF: 0.179 Hom.: 356

Bravo AF: 0.153

Asia WGS AF: 0.113 AC: 395 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.4
DANN	Benign	0.28
PhyloP100		-2.6
PromoterAI		0.19	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4646953; hg19: chr10-94333955;