11-68120912-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_001277.3(CHKA):c.266G>A(p.Arg89His) variant causes a missense change. The variant allele was found at a frequency of 0.000000923 in 1,083,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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. R89L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 9.2e-7 ( 0 hom. )

Consequence

CHKA
NM_001277.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.27

Publications

0 publications found

Variant links:

Genes affected

CHKA (HGNC:1937): (choline kinase alpha) The major pathway for the biosynthesis of phosphatidylcholine occurs via the CDP-choline pathway. The protein encoded by this gene is the initial enzyme in the sequence and may play a regulatory role. The encoded protein also catalyzes the phosphorylation of ethanolamine. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

CHKA Gene-Disease associations (from GenCC):

neurodevelopmental disorder with microcephaly, movement abnormalities, and seizures
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

CHKA links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 3 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.0029 (below the threshold of 3.09). Trascript score misZ: -0.65357 (below the threshold of 3.09). GenCC associations: The gene is linked to neurodevelopmental disorder with microcephaly, movement abnormalities, and seizures.

BP4

Computational evidence support a benign effect (MetaRNN=0.276884).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001277.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHKA	NM_001277.3	MANE Select	c.266G>A	p.Arg89His	missense	Exon 1 of 12	NP_001268.2
CHKA	NM_001376219.1		c.266G>A	p.Arg89His	missense	Exon 1 of 13	NP_001363148.1
CHKA	NM_212469.2		c.266G>A	p.Arg89His	missense	Exon 1 of 11	NP_997634.1	P35790-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHKA	ENST00000265689.9	TSL:1 MANE Select	c.266G>A	p.Arg89His	missense	Exon 1 of 12	ENSP00000265689.4	P35790-1
CHKA	ENST00000356135.9	TSL:1	c.266G>A	p.Arg89His	missense	Exon 1 of 11	ENSP00000348454.4	P35790-2
CHKA	ENST00000931669.1		c.266G>A	p.Arg89His	missense	Exon 1 of 12	ENSP00000601728.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.23e-7

AC:

AN:

1083774

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

526018

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

21958

American (AMR)

AF:

0.00

AC:

AN:

16324

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12742

East Asian (EAS)

AF:

0.00

AC:

AN:

20924

South Asian (SAS)

AF:

0.00

AC:

AN:

34000

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21338

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4230

European-Non Finnish (NFE)

AF:

0.00000110

AC:

AN:

911792

Other (OTH)

AF:

0.00

AC:

AN:

40466

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.093

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.37

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.80

M_CAP

Pathogenic

0.67

MetaRNN

Benign

0.28

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

PhyloP100

4.3

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.69

REVEL

Benign

0.020

Sift

Benign

0.16

Sift4G

Benign

0.18

Polyphen

0.061

Vest4

0.34

MutPred

0.42

Loss of MoRF binding (P = 0.0323)

MVP

0.61

MPC

0.61

ClinPred

0.48

GERP RS

1.8

PromoterAI

-0.037

Neutral

(source)

Varity_R

0.22

gMVP

0.40

Mutation Taster

=59/41

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over