rs758157294

chr15-40652039-G-Cchr15-40652039-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_144508.5(KNL1):c.6349G>C(p.Asp2117His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,410 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2117Y) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KNL1 NM_144508.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.04

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-40652039-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 495234.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2346409).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KNL1	NM_144508.5	c.6349G>C	p.Asp2117His	missense_variant	21/26	ENST00000399668.7
KNL1	NM_170589.5	c.6427G>C	p.Asp2143His	missense_variant	22/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KNL1	ENST00000399668.7	c.6349G>C	p.Asp2117His	missense_variant	21/26	1	NM_144508.5	A2
KNL1	ENST00000346991.9	c.6427G>C	p.Asp2143His	missense_variant	22/27	1		P4
KNL1	ENST00000526913.5	c.3484G>C	p.Asp1162His	missense_variant, NMD_transcript_variant	12/18	1
KNL1	ENST00000532347.1	n.429G>C		non_coding_transcript_exon_variant	4/5	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249506 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461410 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 727024

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000827 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.42
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.21	T;.
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.97	N;N
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Benign	0.069
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.043	D;D
Polyphen		0.61	P;P
Vest4		0.36
MutPred		0.32		Loss of solvent accessibility (P = 0.0442);.;
MVP		0.58
MPC		0.24
ClinPred		0.89	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.35

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

Publications

LitVar

Other links and lift over

dbSNP: rs758157294; hg19: chr15-40944237;