11-68070768-C-G

Variant names:

• chr11-68070768-C-G
• NM_001277.3:c.720G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001277.3(CHKA):​c.720G>C​(p.Met240Ile) variant causes a missense change involving the alteration of a 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: 32)
• Consequence: CHKA NM_001277.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.80
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHKA	NM_001277.3	MANE Select	c.720G>C	p.Met240Ile	missense	Exon 5 of 12	NP_001268.2
	CHKA	NM_001376219.1		c.750G>C	p.Met250Ile	missense	Exon 6 of 13	NP_001363148.1
	CHKA	NM_212469.2		c.666G>C	p.Met222Ile	missense	Exon 4 of 11	NP_997634.1	P35790-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHKA	ENST00000265689.9	TSL:1 MANE Select	c.720G>C	p.Met240Ile	missense	Exon 5 of 12	ENSP00000265689.4	P35790-1
	CHKA	ENST00000356135.9	TSL:1	c.666G>C	p.Met222Ile	missense	Exon 4 of 11	ENSP00000348454.4	P35790-2
	CHKA	ENST00000931669.1		c.720G>C	p.Met240Ile	missense	Exon 5 of 12	ENSP00000601728.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.3	L
PhyloP100		7.8
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.27
Sift	Benign	0.17	T
Sift4G	Benign	0.37	T
Polyphen		0.94	P
Vest4		0.83
MutPred		0.51		Loss of disorder (P = 0.0564)
MVP		0.57
MPC		1.4
ClinPred		0.91	D
GERP RS		5.4
Varity_R		0.57
gMVP		0.72
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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

hg19: chr11-67838235;