rs1554042050

chr5-62361328-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_001098511.3(KIF2A):c.959C>T(p.Thr320Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KIF2A NM_001098511.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.91

Genes affected

KIF2A (HGNC:6318): (kinesin family member 2A) The protein encoded by this gene is a plus end-directed motor required for normal mitotic progression. The encoded protein is required for normal spindle activity during mitosis and is necessary for normal brain development. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

DIMT1 (HGNC:30217): (DIM1 rRNA methyltransferase and ribosome maturation factor) The protein encoded by this gene is a methyltransferase that is responsible for dimethylation of adjacent adenosines near the 18S rRNA decoding site. The encoded protein is essential for ribosome biogenesis, although its catalytic activity is not involved in the process. The yeast ortholog of this protein functions in the cytoplasm while this protein functions in the nucleus. [provided by RefSeq, Jan 2017]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a binding_site (size 7) in uniprot entity KIF2A_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001098511.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 5-62361328-C-T is Pathogenic according to our data. Variant chr5-62361328-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 435642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF2A	NM_001098511.3	c.959C>T	p.Thr320Ile	missense_variant	10/21	ENST00000407818.8
KIF2A	NM_004520.5	c.959C>T	p.Thr320Ile	missense_variant	10/20
KIF2A	NM_001243953.2	c.902C>T	p.Thr301Ile	missense_variant	10/20
KIF2A	NM_001243952.2	c.878C>T	p.Thr293Ile	missense_variant	11/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF2A	ENST00000407818.8	c.959C>T	p.Thr320Ile	missense_variant	10/21	1	NM_001098511.3	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Complex cortical dysplasia with other brain malformations 3 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	May 03, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 31, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 24, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;.;.;.;T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;T
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Pathogenic	5.1	H;.;H;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.7	D;D;D;D;N
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;T
Polyphen		0.99	D;.;D;.;.
Vest4		0.94
MutPred		0.93		Loss of disorder (P = 0.0572);.;Loss of disorder (P = 0.0572);.;.;
MVP		0.80
MPC		1.9
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.96
gMVP		0.95

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: rs1554042050; hg19: chr5-61657155;