5-62306494-A-G

Position:

• chr5-62306494-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4 BP6

The NM_001098511.3(KIF2A):​c.22A>G​(p.Lys8Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000072 in 1,389,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: KIF2A NM_001098511.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.13

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31310853).
• BP6: Variant 5-62306494-A-G is Benign according to our data. Variant chr5-62306494-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2539517.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF2A	NM_001098511.3	c.22A>G	p.Lys8Glu	missense_variant	1/21	ENST00000407818.8	NP_001091981.1
KIF2A	NM_004520.5	c.22A>G	p.Lys8Glu	missense_variant	1/20		NP_004511.2
KIF2A	NM_001243953.2	c.22A>G	p.Lys8Glu	missense_variant	1/20		NP_001230882.1
KIF2A	NM_001243952.2	c.-263A>G		5_prime_UTR_variant	1/21		NP_001230881.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF2A	ENST00000407818.8	c.22A>G	p.Lys8Glu	missense_variant	1/21	1	NM_001098511.3	ENSP00000385000.3
ENSG00000288643	ENST00000509663.2	n.22A>G		non_coding_transcript_exon_variant	1/6	3		ENSP00000502199.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.20e-7 AC: 1 AN: 1389744 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 685446

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.31e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2023

The c.22A>G (p.K8E) alteration is located in exon 1 (coding exon 1) of the KIF2A gene. This alteration results from a A to G substitution at nucleotide position 22, causing the lysine (K) at amino acid position 8 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Benign	0.84
DEOGEN2	Benign	0.051	T;T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.072
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.80	T;T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.2	L;.;L
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.49	N;N;N
REVEL	Benign	0.10
Sift	Benign	0.62	T;T;T
Sift4G	Benign	0.68	T;T;T
Polyphen		0.55	P;.;B
Vest4		0.34
MutPred		0.42		Loss of methylation at K8 (P = 0.0067);Loss of methylation at K8 (P = 0.0067);Loss of methylation at K8 (P = 0.0067);
MVP		0.89
MPC		1.4
ClinPred		0.40	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.85

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: rs972154930; hg19: chr5-61602321;