5-62348083-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001098511.3(KIF2A):c.195C>A(p.Asp65Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,613,756 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (9 hom.)
• Consequence: KIF2A NM_001098511.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.83

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007913381).
• BP6: Variant 5-62348083-C-A is Benign according to our data. Variant chr5-62348083-C-A is described in ClinVar as [Benign]. Clinvar id is 382901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00627 (955/152276) while in subpopulation AFR AF= 0.0221 (918/41548). AF 95% confidence interval is 0.0209. There are 8 homozygotes in gnomad4. There are 464 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 954 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF2A	NM_001098511.3	c.195C>A	p.Asp65Glu	missense_variant	3/21	ENST00000407818.8
KIF2A	NM_004520.5	c.195C>A	p.Asp65Glu	missense_variant	3/20
KIF2A	NM_001243953.2	c.195C>A	p.Asp65Glu	missense_variant	3/20
KIF2A	NM_001243952.2	c.114C>A	p.Asp38Glu	missense_variant	4/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF2A	ENST00000407818.8	c.195C>A	p.Asp65Glu	missense_variant	3/21	1	NM_001098511.3	A1

Frequencies

GnomAD3 genomes AF: 0.00627 AC: 954 AN: 152158 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0221

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00158 AC: 397 AN: 251154 Hom.: 2 AF XY: 0.00119 AC XY: 161 AN XY: 135728

Gnomad AFR exome AF: 0.0226

Gnomad AMR exome AF: 0.000752

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: 0.000490

GnomAD4 exome AF: 0.000629 AC: 919 AN: 1461480 Hom.: 9 Cov.: 30 AF XY: 0.000552 AC XY: 401 AN XY: 727036

Gnomad4 AFR exome AF: 0.0238

Gnomad4 AMR exome AF: 0.000872

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: 0.00000989

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.00627 AC: 955 AN: 152276 Hom.: 8 Cov.: 32 AF XY: 0.00623 AC XY: 464 AN XY: 74458

Gnomad4 AFR AF: 0.0221

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00124 Hom.: 2

Bravo AF: 0.00703

ESP6500AA AF: 0.0207 AC: 91

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00194 AC: 235

Asia WGS AF: 0.00144 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 02, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

KIF2A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 31, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.040	T;.;T;.;.;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.038
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.86	D;D;T;D;D;T
MetaRNN	Benign	0.0079	T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.73	N;.;.;N;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.6	N;N;N;N;N;N
REVEL	Benign	0.19
Sift	Benign	0.81	T;T;T;T;D;T
Sift4G	Benign	0.66	T;T;T;T;D;T
Polyphen		0.44	B;.;.;B;.;.
Vest4		0.57
MutPred		0.12		Gain of phosphorylation at S61 (P = 0.191);.;Gain of phosphorylation at S61 (P = 0.191);Gain of phosphorylation at S61 (P = 0.191);.;.;
MVP		0.47
MPC		1.4
ClinPred		0.019	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.32

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: rs73102041; hg19: chr5-61643910;