15-40602927-CAAA-CAA
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2
The NM_144508.5(KNL1):c.1delA(p.Met1fs) variant causes a frameshift, start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,432,768 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 7.0e-7 ( 0 hom. )
Consequence
KNL1
NM_144508.5 frameshift, start_lost
NM_144508.5 frameshift, start_lost
Scores
Not classified
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 0.133
Publications
0 publications found
Genes affected
KNL1 (HGNC:24054): (kinetochore scaffold 1) The protein encoded by this gene is a component of the multiprotein assembly that is required for creation of kinetochore-microtubule attachments and chromosome segregation. The encoded protein functions as a scaffold for proteins that influence the spindle assembly checkpoint during the eukaryotic cell cycle and it interacts with at least five different kinetochore proteins and two checkpoint kinases. In adults, this gene is predominantly expressed in normal testes, various cancer cell lines and primary tumors from other tissues and is ubiquitously expressed in fetal tissues. This gene was originally identified as a fusion partner with the mixed-lineage leukemia (MLL) gene in t(11;15)(q23;q14). Mutations in this gene cause autosomal recessive primary microcephaly-4 (MCPH4). Alternative splicing results in multiple transcript variants encoding different isoforms. Additional splice variants have been described but their biological validity has not been confirmed. [provided by RefSeq, Jan 2013]
KNL1 Gene-Disease associations (from GenCC):
- microcephaly 4, primary, autosomal recessiveInheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
- autosomal recessive primary microcephalyInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 10 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 22 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.98e-7 AC: 1AN: 1432768Hom.: 0 Cov.: 25 AF XY: 0.00000140 AC XY: 1AN XY: 714112 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1432768
Hom.:
Cov.:
25
AF XY:
AC XY:
1
AN XY:
714112
show subpopulations
African (AFR)
AF:
AC:
0
AN:
32498
American (AMR)
AF:
AC:
0
AN:
43056
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25764
East Asian (EAS)
AF:
AC:
0
AN:
39424
South Asian (SAS)
AF:
AC:
0
AN:
83614
European-Finnish (FIN)
AF:
AC:
0
AN:
52990
Middle Eastern (MID)
AF:
AC:
0
AN:
5612
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1090470
Other (OTH)
AF:
AC:
0
AN:
59340
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Not reported inComputational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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