5-62348105-G-A

Position:

• chr5-62348105-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_001098511.3(KIF2A):​c.217G>A​(p.Glu73Lys) 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KIF2A NM_001098511.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.85

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]

ENSG00000288643 (HGNC:):

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-62348105-G-A is Pathogenic according to our data. Variant chr5-62348105-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1031823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.13964316). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF2A	NM_001098511.3	c.217G>A	p.Glu73Lys	missense_variant	3/21	ENST00000407818.8	NP_001091981.1
KIF2A	NM_004520.5	c.217G>A	p.Glu73Lys	missense_variant	3/20		NP_004511.2
KIF2A	NM_001243953.2	c.217G>A	p.Glu73Lys	missense_variant	3/20		NP_001230882.1
KIF2A	NM_001243952.2	c.136G>A	p.Glu46Lys	missense_variant	4/21		NP_001230881.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF2A	ENST00000407818.8	c.217G>A	p.Glu73Lys	missense_variant	3/21	1	NM_001098511.3	ENSP00000385000.3
ENSG00000288643	ENST00000509663.2	n.64+41569G>A		intron_variant		3		ENSP00000502199.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Complex cortical dysplasia with other brain malformations 3 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Nov 10, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 31, 2018	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	T;.;T;.;.;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.017
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.14	T;T;T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.34	N;.;.;N;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.64	N;N;N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.68	T;T;T;T;T;T
Sift4G	Benign	0.91	T;T;T;T;T;T
Polyphen		0.0090	B;.;.;B;.;.
Vest4		0.42
MutPred		0.27		Gain of ubiquitination at E73 (P = 9e-04);.;Gain of ubiquitination at E73 (P = 9e-04);Gain of ubiquitination at E73 (P = 9e-04);.;.;
MVP		0.52
MPC		1.0
ClinPred		0.68	D
GERP RS		5.4
Varity_R		0.14
gMVP		0.27

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: rs1747667870; hg19: chr5-61643932;