chr18-58481836-T-G

Variant names:

• chr18-58481836-T-G
• rs2051312795
• NM_052947.4:c.6500A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_052947.4(ALPK2):​c.6500A>C​(p.Glu2167Ala) 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E2167K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALPK2 NM_052947.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0930
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06519824).

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.6500A>C	p.Glu2167Ala	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.6500A>C	p.Glu2167Ala	missense	Exon 13 of 13	ENSP00000354991.3	Q86TB3
	ALPK2	ENST00000941324.1		c.6464A>C	p.Glu2155Ala	missense	Exon 12 of 12	ENSP00000611383.1
	ALPK2	ENST00000857519.1		c.3407A>C	p.Glu1136Ala	missense	Exon 13 of 13	ENSP00000527578.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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	Benign	0.10
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	5.0
DANN	Benign	0.93
DEOGEN2	Benign	0.0074	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.093
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.060
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.035	D
Polyphen		0.18	B
Vest4		0.10
MutPred		0.15		Gain of MoRF binding (P = 0.012)
MVP		0.25
MPC		0.12
ClinPred		0.23	T
GERP RS		0.56
Varity_R		0.085
gMVP		0.26
Mutation Taster		=100/0	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: rs2051312795; hg19: chr18-56149068;