15-40621478-AT-GC

Variant names:

• chr15-40621478-AT-GC
• NM_144508.5:c.1214_1215delATinsGC
• KNL1 p.Asp405Gly

Variant summary

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

The NM_144508.5(KNL1):​c.1214_1215delATinsGC​(p.Asp405Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KNL1 NM_144508.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.63
• 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 recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144508.5. 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
	KNL1	NM_144508.5	MANE Select	c.1214_1215delATinsGC	p.Asp405Gly	missense	N/A	NP_653091.3	Q8NG31-2
	KNL1	NM_170589.5		c.1292_1293delATinsGC	p.Asp431Gly	missense	N/A	NP_733468.3	Q8NG31-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KNL1	ENST00000399668.7	TSL:1 MANE Select	c.1214_1215delATinsGC	p.Asp405Gly	missense	N/A	ENSP00000382576.3	Q8NG31-2
	KNL1	ENST00000346991.9	TSL:1	c.1292_1293delATinsGC	p.Asp431Gly	missense	N/A	ENSP00000335463.6	Q8NG31-1
	KNL1	ENST00000533001.1	TSL:1	n.1359_1360delATinsGC		non_coding_transcript_exon	Exon 10 of 10

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr15-40913676;