11-46809784-T-G

Variant names:

• chr11-46809784-T-G
• rs193921076
• NM_001008938.4:c.721A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001008938.4(CKAP5):​c.721A>C​(p.Lys241Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K241E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CKAP5 NM_001008938.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.59
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.421148).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CKAP5	NM_001008938.4	c.721A>C	p.Lys241Gln	missense_variant	Exon 6 of 44	ENST00000529230.6	NP_001008938.1
CKAP5	NM_014756.4	c.721A>C	p.Lys241Gln	missense_variant	Exon 6 of 43		NP_055571.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CKAP5	ENST00000529230.6	c.721A>C	p.Lys241Gln	missense_variant	Exon 6 of 44	5	NM_001008938.4	ENSP00000432768.1
CKAP5	ENST00000354558.7	c.721A>C	p.Lys241Gln	missense_variant	Exon 5 of 42	1		ENSP00000346566.3
CKAP5	ENST00000312055.9	c.721A>C	p.Lys241Gln	missense_variant	Exon 6 of 43	5		ENSP00000310227.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;.
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.42	T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.8	L;L;L
PhyloP100		7.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.24
Sift	Benign	0.050	D;D;D
Sift4G	Benign	0.13	T;T;T
Vest4		0.49
ClinPred		0.82	D
GERP RS		5.8
Varity_R		0.39
gMVP		0.33
Mutation Taster		=71/29	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

Other links and lift over

dbSNP: rs193921076; hg19: chr11-46831334;