11-46752683-G-T

Position:

• chr11-46752683-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001008938.4(CKAP5):​c.5085C>A​(p.Ser1695Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CKAP5 NM_001008938.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.772

Genes affected

CKAP5 (HGNC:28959): (cytoskeleton associated protein 5) This gene encodes a cytoskeleton-associated protein which belongs to the TOG/XMAP215 family. The N-terminal half of this protein contains a microtubule-binding domain and the C-terminal half contains a KXGS motif for binding tubulin dimers. This protein has two distinct roles in spindle formation; it protects kinetochore microtubules from depolymerization and plays an essential role in centrosomal microtubule assembly. This protein may be necessary for the proper interaction of microtubules with the cell cortex for directional cell movement. It also plays a role in translation of the myelin basic protein (MBP) mRNA by interacting with heterogeneous nuclear ribonucleoprotein (hnRNP) A2, which associates with MBP. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CKAP5	NM_001008938.4	c.5085C>A	p.Ser1695Arg	missense_variant	38/44	ENST00000529230.6	NP_001008938.1
CKAP5	NM_014756.4	c.4905C>A	p.Ser1635Arg	missense_variant	37/43		NP_055571.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CKAP5	ENST00000529230.6	c.5085C>A	p.Ser1695Arg	missense_variant	38/44	5	NM_001008938.4	ENSP00000432768	P1
CKAP5	ENST00000354558.7	c.4905C>A	p.Ser1635Arg	missense_variant	36/42	1		ENSP00000346566
CKAP5	ENST00000533413.5	n.2064C>A		non_coding_transcript_exon_variant	13/19	1
CKAP5	ENST00000312055.9	c.4905C>A	p.Ser1635Arg	missense_variant	37/43	5		ENSP00000310227

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

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

Jan 29, 2024

The c.5085C>A (p.S1695R) alteration is located in exon 38 (coding exon 37) of the CKAP5 gene. This alteration results from a C to A substitution at nucleotide position 5085, causing the serine (S) at amino acid position 1695 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	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;.;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D;D;.
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.55	D;D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.3	M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Benign	0.28
Sift	Uncertain	0.025	D;D;D
Sift4G	Uncertain	0.048	D;D;D
Polyphen		0.84	P;D;D
Vest4		0.71
MutPred		0.54		Loss of helix (P = 0.0558);.;.;
MVP		0.76
MPC		1.5
ClinPred		0.95	D
GERP RS		3.3
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.34
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1168626516; hg19: chr11-46774233;