chr1-44754787-G-A

Variant names:

• chr1-44754787-G-A
• rs376314711
• NM_006845.4:c.701G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006845.4(KIF2C):​c.701G>A​(p.Arg234Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,613,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: KIF2C NM_006845.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.04

Genes affected

KIF2C (HGNC:6393): (kinesin family member 2C) This gene encodes a kinesin-like protein that functions as a microtubule-dependent molecular motor. The encoded protein can depolymerize microtubules at the plus end, thereby promoting mitotic chromosome segregation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.082151055).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF2C	NM_006845.4	c.701G>A	p.Arg234Gln	missense_variant	Exon 8 of 21	ENST00000372224.9	NP_006836.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF2C	ENST00000372224.9	c.701G>A	p.Arg234Gln	missense_variant	Exon 8 of 21	1	NM_006845.4	ENSP00000361298.4

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251424 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461276 Hom.: 0 Cov.: 29 AF XY: 0.0000261 AC XY: 19 AN XY: 726982

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000324 AC: 36 AN: 1111486

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74430

African (AFR) AF: 0.00 AC: 0 AN: 41544

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.0000189

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.701G>A (p.R234Q) alteration is located in exon 8 (coding exon 8) of the KIF2C gene. This alteration results from a G to A substitution at nucleotide position 701, causing the arginine (R) at amino acid position 234 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.021	T;T;T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.057
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T;D;D;D
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.082	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	.;L;.;.
PhyloP100		2.0
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.41	N;N;N;N
REVEL	Benign	0.017
Sift	Benign	0.66	T;T;T;T
Sift4G	Benign	0.62	T;T;T;T
Polyphen		0.089, 0.45	.;B;.;B
Vest4		0.24, 0.27
MVP		0.31
MPC		0.37
ClinPred		0.43	T
GERP RS		4.5
Varity_R		0.14
gMVP		0.50
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs376314711; hg19: chr1-45220459;