Genetic Variant CENPK:p.Asp258Tyr (chr5-65518513-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_022145.5(CENPK):c.772G>T(p.Asp258Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000151 in 1,460,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

CENPK
NM_022145.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.62

Variant links:

Genes affected

CENPK (HGNC:29479): (centromere protein K) CENPK is a subunit of a CENPH (MIM 605607)-CENPI (MIM 300065)-associated centromeric complex that targets CENPA (MIM 117139) to centromeres and is required for proper kinetochore function and mitotic progression (Okada et al., 2006 [PubMed 16622420]).[supplied by OMIM, Mar 2008]

CENPK links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.765

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CENPK	NM_022145.5 link	c.772G>T	p.Asp258Tyr	missense_variant	Exon 11 of 11	ENST00000396679.6	NP_071428.2	Q9BS16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CENPK	ENST00000396679.6 link	c.772G>T	p.Asp258Tyr	missense_variant	Exon 11 of 11	1	NM_022145.5	ENSP00000379911.1		Q9BS16

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249758

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

134982

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1460450

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726462

show subpopulations

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:

0.0000171

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.772G>T (p.D258Y) alteration is located in exon 11 (coding exon 9) of the CENPK gene. This alteration results from a G to T substitution at nucleotide position 772, causing the aspartic acid (D) at amino acid position 258 to be replaced by a tyrosine (Y). 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

Uncertain

0.39

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

D;D;D;.;T

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.91

.;.;D;D;D

M_CAP

Benign

0.0079

MetaRNN

Pathogenic

0.77

D;D;D;D;D

MetaSVM

Uncertain

-0.16

MutationAssessor

Uncertain

2.8

M;M;M;.;.

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-7.1

D;D;D;D;D

REVEL

Pathogenic

0.72

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D;D

Polyphen

1.0

D;D;D;.;.

Vest4

0.67

MutPred

0.67

Loss of disorder (P = 0.0195);Loss of disorder (P = 0.0195);Loss of disorder (P = 0.0195);.;.;

MVP

0.53

MPC

0.43

ClinPred

0.97

GERP RS

5.7

Varity_R

0.91

gMVP

0.90

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