NM_144508.5:c.165C>G

Variant names:

• chr15-40608876-C-G
• rs201818761
• NM_144508.5:c.165C>G

Variant summary

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

The NM_144508.5(KNL1):​c.165C>G​(p.Asn55Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N55N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: KNL1 NM_144508.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.541
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

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 (MetaRNN=0.09256834).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNL1	NM_144508.5	c.165C>G	p.Asn55Lys	missense_variant	Exon 5 of 26	ENST00000399668.7	NP_653091.3
KNL1	NM_170589.5	c.165C>G	p.Asn55Lys	missense_variant	Exon 5 of 27		NP_733468.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNL1	ENST00000399668.7	c.165C>G	p.Asn55Lys	missense_variant	Exon 5 of 26	1	NM_144508.5	ENSP00000382576.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.058	T;T;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.65	T;T;T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.093	T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.54
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.038
Sift	Benign	0.18	T;T;T
Sift4G	Benign	0.081	T;D;D
Polyphen		0.76	P;.;P
Vest4		0.37
MutPred		0.21		Gain of methylation at N55 (P = 0.0376);Gain of methylation at N55 (P = 0.0376);Gain of methylation at N55 (P = 0.0376);
MVP		0.33
MPC		0.082
ClinPred		0.27	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.096
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201818761; hg19: chr15-40901074;