2-148875627-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_004522.3(KIF5C):c.10C>A(p.Pro4Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000155 in 1,287,448 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: KIF5C NM_004522.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.52

Genes affected

KIF5C (HGNC:6325): (kinesin family member 5C) The protein encoded by this gene is a kinesin heavy chain subunit involved in the transport of cargo within the central nervous system. The encoded protein, which acts as a tetramer by associating with another heavy chain and two light chains, interacts with protein kinase CK2. Mutations in this gene have been associated with complex cortical dysplasia with other brain malformations-2. Two transcript variants, one protein-coding and the other non-protein coding, have been found for this gene. [provided by RefSeq, Jul 2015]

KIF5C-AS1 (HGNC:40325): (KIF5C antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, KIF5C
• BP4: Computational evidence support a benign effect (MetaRNN=0.25062662).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF5C	NM_004522.3	c.10C>A	p.Pro4Thr	missense_variant	1/26	ENST00000435030.6
KIF5C-AS1	XR_001739733.2	n.7691G>T		non_coding_transcript_exon_variant	4/4
KIF5C	XM_017004062.2	c.10C>A	p.Pro4Thr	missense_variant	1/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF5C	ENST00000435030.6	c.10C>A	p.Pro4Thr	missense_variant	1/26	1	NM_004522.3	P4
KIF5C-AS1	ENST00000601658.5	n.676+1599G>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000155 AC: 2 AN: 1287448 Hom.: 0 Cov.: 35 AF XY: 0.00000315 AC XY: 2 AN XY: 634270

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000310

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: 9.90e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 11, 2023

Variant summary: KIF5C c.10C>A (p.Pro4Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. To our knowledge, no occurrence of c.10C>A in individuals affected with Complex Cortical Dysplasia With Other Brain Malformations 2 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.021
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.66	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.28
Sift	Benign	0.037	D
Sift4G	Uncertain	0.057	T
Polyphen		0.017	B
Vest4		0.28
MutPred		0.17		Loss of disorder (P = 0.0761);
MVP		0.86
MPC		0.94
ClinPred		0.75	D
GERP RS		4.1
Varity_R		0.22
gMVP		0.63

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: chr2-149633196;