18-58481827-G-A

Variant names:

• chr18-58481827-G-A
• rs2051312750
• NM_052947.4:c.6509C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_052947.4(ALPK2):​c.6509C>T​(p.Thr2170Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 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. T2170N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALPK2 NM_052947.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.78
• Publications: 0 publications found

Genes affected

ALPK2 (HGNC:20565): (alpha kinase 2) Predicted to enable ATP binding activity; protein serine kinase activity; and protein serine/threonine kinase activity. Involved in several processes, including epicardium morphogenesis; heart development; and negative regulation of Wnt signaling pathway involved in heart development. Acts upstream of or within regulation of gene expression. Colocalizes with basolateral plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000296058 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24495584).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052947.4. 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
	ALPK2	NM_052947.4	MANE Select	c.6509C>T	p.Thr2170Ile	missense	Exon 13 of 13	NP_443179.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALPK2	ENST00000361673.4	TSL:1 MANE Select	c.6509C>T	p.Thr2170Ile	missense	Exon 13 of 13	ENSP00000354991.3	Q86TB3
	ALPK2	ENST00000941324.1		c.6473C>T	p.Thr2158Ile	missense	Exon 12 of 12	ENSP00000611383.1
	ALPK2	ENST00000857519.1		c.3416C>T	p.Thr1139Ile	missense	Exon 13 of 13	ENSP00000527578.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.038	T
Eigen	Benign	0.052
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.8
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.12
MutPred		0.16		Loss of phosphorylation at T2170 (P = 0.0016)
MVP		0.79
MPC		0.49
ClinPred		0.98	D
GERP RS		-0.12
Varity_R		0.25
gMVP		0.26
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs2051312750; hg19: chr18-56149059;