18-58481867-T-A

Variant names:

• chr18-58481867-T-A
• rs7240666
• NM_052947.4:c.6469A>T

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.6469A>T​(p.Ile2157Leu) 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. 16/22 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. I2157V) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALPK2 NM_052947.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.491
• Publications: 27 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=0.063703865).

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.6469A>T	p.Ile2157Leu	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.6469A>T	p.Ile2157Leu	missense	Exon 13 of 13	ENSP00000354991.3	Q86TB3
	ALPK2	ENST00000941324.1		c.6433A>T	p.Ile2145Leu	missense	Exon 12 of 12	ENSP00000611383.1
	ALPK2	ENST00000857519.1		c.3376A>T	p.Ile1126Leu	missense	Exon 13 of 13	ENSP00000527578.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 61

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 172625

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.5
DANN	Benign	0.83
DEOGEN2	Benign	0.0040	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.14	T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.49
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.043
Sift	Benign	0.079	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.072		Loss of MoRF binding (P = 0.1002)
MVP		0.10
MPC		0.094
ClinPred		0.15	T
GERP RS		2.8
Varity_R		0.052
gMVP		0.13
Mutation Taster		=99/1	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: rs7240666; hg19: chr18-56149099;