Genetic Variant KIFC1:p.Arg241Gln (chr6-33404095-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002263.4(KIFC1):c.722G>A(p.Arg241Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

KIFC1
NM_002263.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.32

Variant links:

Genes affected

KIFC1 (HGNC:6389): (kinesin family member C1) Predicted to enable microtubule binding activity and minus-end-directed microtubule motor activity. Involved in mitotic metaphase plate congression and mitotic spindle assembly. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

KIFC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20868939).

BS2

High AC in GnomAdExome4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIFC1	NM_002263.4 link	c.722G>A	p.Arg241Gln	missense_variant	Exon 6 of 11	ENST00000428849.7	NP_002254.2	Q9BW19A0A024RCS7
KIFC1	XM_011514585.2 link	c.722G>A	p.Arg241Gln	missense_variant	Exon 6 of 12		XP_011512887.1
KIFC1	XM_017010837.2 link	c.599G>A	p.Arg200Gln	missense_variant	Exon 6 of 11		XP_016866326.2
KIFC1	XM_011514587.3 link	c.722G>A	p.Arg241Gln	missense_variant	Exon 6 of 10		XP_011512889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KIFC1	ENST00000428849.7 link	c.722G>A	p.Arg241Gln	missense_variant	Exon 6 of 11	1	NM_002263.4	ENSP00000393963.2	Q9BW19
KIFC1	ENST00000450504.1 link	c.*236G>A		downstream_gene_variant		3		ENSP00000409539.1	A2AB20
KIFC1	ENST00000486695.1 link	n.*229G>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

250784

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135506

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1461524

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727058

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000566

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.722G>A (p.R241Q) alteration is located in exon 6 (coding exon 6) of the KIFC1 gene. This alteration results from a G to A substitution at nucleotide position 722, causing the arginine (R) at amino acid position 241 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

0.066

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.018

Eigen

Benign

-0.063

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.28

M_CAP

Benign

0.076

MetaRNN

Benign

0.21

MetaSVM

Benign

-0.72

MutationAssessor

Uncertain

2.4

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.28

REVEL

Uncertain

0.34

Sift

Benign

0.37

Sift4G

Benign

0.30

Polyphen

1.0

Vest4

0.20

MutPred

0.46

Loss of MoRF binding (P = 0.0637);

MVP

0.82

MPC

0.46

ClinPred

0.19

GERP RS

4.3

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.055

gMVP

0.36

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over