chr8-144473433-T-C

Position:

• chr8-144473433-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000301332.3(KIFC2):​c.2500T>C​(p.Cys834Arg) 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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KIFC2 ENST00000301332.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.17

Genes affected

KIFC2 (HGNC:29530): (kinesin family member C2) Predicted to enable microtubule binding activity and microtubule motor activity. Predicted to be involved in microtubule-based movement and mitotic spindle assembly. Predicted to be located in cytoplasm. Predicted to be part of kinesin complex. Predicted to be active in microtubule cytoskeleton and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

FOXH1 (HGNC:3814): (forkhead box H1) FOXH1 encodes a human homolog of Xenopus forkhead activin signal transducer-1. FOXH1 protein binds SMAD2 and activates an activin response element via binding the DNA motif TGT(G/T)(T/G)ATT. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26478598).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIFC2	NM_001369769.2	c.*44T>C		3_prime_UTR_variant	18/18	ENST00000645548.2
FOXH1	NM_003923.3	c.*805A>G		3_prime_UTR_variant	3/3	ENST00000377317.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIFC2	ENST00000301332.3	c.2500T>C	p.Cys834Arg	missense_variant	17/17	1
FOXH1	ENST00000377317.5	c.*805A>G		3_prime_UTR_variant	3/3	1	NM_003923.3	P1
KIFC2	ENST00000645548.2	c.*44T>C		3_prime_UTR_variant	18/18		NM_001369769.2	P1
KIFC2	ENST00000643461.1	n.2877T>C		non_coding_transcript_exon_variant	17/17

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1391918 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 687880

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 01, 2024

The c.2500T>C (p.C834R) alteration is located in exon 17 (coding exon 17) of the KIFC2 gene. This alteration results from a T to C substitution at nucleotide position 2500, causing the cysteine (C) at amino acid position 834 to be replaced by an arginine (R). 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	0.11
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0027	T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.0022
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.32	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D
Polyphen		0.26	B
Vest4		0.51
MutPred		0.30		Loss of catalytic residue at W835 (P = 4e-04);
MVP		0.74
ClinPred		0.50	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.85
gMVP		0.24

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: chr8-145698816;