Genetic Variant ALPK2:p.Val1086Ile (chr18-58536931-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_052947.4(ALPK2):c.3256G>A(p.Val1086Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★). Synonymous variant affecting the same amino acid position (i.e. V1086V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

ALPK2
NM_052947.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.402

Variant links:

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]

ALPK2 links:

ENSG00000267257 (HGNC:):

ENSG00000267257 links:

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ACMG classification

Classification was made for transcript

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=0.10914102).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPK2	NM_052947.4 link	c.3256G>A	p.Val1086Ile	missense_variant	Exon 5 of 13	ENST00000361673.4	NP_443179.3	Q86TB3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ALPK2	ENST00000361673.4 link	c.3256G>A	p.Val1086Ile	missense_variant	Exon 5 of 13	1	NM_052947.4	ENSP00000354991.3	Q86TB3
ALPK2	ENST00000589204.1 link	n.189G>A		non_coding_transcript_exon_variant	Exon 1 of 2	2
ENSG00000267257	ENST00000591360.1 link	n.932C>T		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000797

AC:

AN:

250826

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000899

AC:

AN:

1112000

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 01, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3256G>A (p.V1086I) alteration is located in exon 5 (coding exon 4) of the ALPK2 gene. This alteration results from a G to A substitution at nucleotide position 3256, causing the valine (V) at amino acid position 1086 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

4.6

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.018

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.49

M_CAP

Benign

0.011

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.97

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.38

REVEL

Benign

0.036

Sift

Benign

0.060

Sift4G

Benign

0.40

Polyphen

0.80

Vest4

0.043

MutPred

0.27

Loss of disorder (P = 0.1201);

MVP

0.41

MPC

0.20

ClinPred

0.21

GERP RS

2.6

Varity_R

0.034

gMVP

0.049

Mutation Taster

=96/4

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

chr18-58536931-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over