5-62348135-G-A

Position:

• chr5-62348135-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001098511.3(KIF2A):​c.247G>A​(p.Ala83Thr) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KIF2A NM_001098511.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.101

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.012268186).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF2A	NM_001098511.3	c.247G>A	p.Ala83Thr	missense_variant	3/21	ENST00000407818.8	NP_001091981.1
KIF2A	NM_004520.5	c.247G>A	p.Ala83Thr	missense_variant	3/20		NP_004511.2
KIF2A	NM_001243953.2	c.247G>A	p.Ala83Thr	missense_variant	3/20		NP_001230882.1
KIF2A	NM_001243952.2	c.166G>A	p.Ala56Thr	missense_variant	4/21		NP_001230881.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF2A	ENST00000407818.8	c.247G>A	p.Ala83Thr	missense_variant	3/21	1	NM_001098511.3	ENSP00000385000.3
ENSG00000288643	ENST00000509663.2	n.64+41599G>A		intron_variant		3		ENSP00000502199.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 07, 2022

This variant has not been reported in the literature in individuals affected with KIF2A-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 83 of the KIF2A protein (p.Ala83Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	0.97
DANN	Benign	0.39
DEOGEN2	Benign	0.021	T;.;T;.;.;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.82	T;T;T;T;D;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.012	T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.1	N;.;.;N;.;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.090	N;N;N;N;N;N
REVEL	Benign	0.086
Sift	Benign	0.65	T;T;T;T;T;T
Sift4G	Benign	0.76	T;T;T;T;T;T
Polyphen		0.0	B;.;.;B;.;.
Vest4		0.16
MutPred		0.16		Gain of glycosylation at A83 (P = 0.0042);.;Gain of glycosylation at A83 (P = 0.0042);Gain of glycosylation at A83 (P = 0.0042);.;.;
MVP		0.46
MPC		0.83
ClinPred		0.041	T
GERP RS		-6.3
Varity_R		0.019
gMVP		0.14

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-61643962;