18-58481867-T-C

Position:

• chr18-58481867-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The ENST00000361673.4(ALPK2):​c.6469A>G​(p.Ile2157Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.837 in 1,613,966 control chromosomes in the GnomAD database, including 566,753 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2157K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.86 (56089 hom., cov: 32)
  • Exomes 𝑓: 0.83 (510664 hom.)
• Consequence: ALPK2 ENST00000361673.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.491

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2549042E-6).
• BP6: Variant 18-58481867-T-C is Benign according to our data. Variant chr18-58481867-T-C is described in ClinVar as [Benign]. Clinvar id is 3060101.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr18-58481867-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALPK2	NM_052947.4	c.6469A>G	p.Ile2157Val	missense_variant	13/13	ENST00000361673.4	NP_443179.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALPK2	ENST00000361673.4	c.6469A>G	p.Ile2157Val	missense_variant	13/13	1	NM_052947.4	ENSP00000354991	P1

Frequencies

GnomAD3 genomes AF: 0.856 AC: 130272 AN: 152112 Hom.: 56028 Cov.: 32

Gnomad AFR AF: 0.886

Gnomad AMI AF: 0.873

Gnomad AMR AF: 0.871

Gnomad ASJ AF: 0.768

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.968

Gnomad FIN AF: 0.878

Gnomad MID AF: 0.794

Gnomad NFE AF: 0.818

Gnomad OTH AF: 0.846

GnomAD3 exomes AF: 0.868 AC: 218192 AN: 251312 Hom.: 95300 AF XY: 0.868 AC XY: 117892 AN XY: 135826

Gnomad AFR exome AF: 0.884

Gnomad AMR exome AF: 0.908

Gnomad ASJ exome AF: 0.768

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.962

Gnomad FIN exome AF: 0.882

Gnomad NFE exome AF: 0.815

Gnomad OTH exome AF: 0.845

GnomAD4 exome AF: 0.834 AC: 1219701 AN: 1461736 Hom.: 510664 Cov.: 61 AF XY: 0.837 AC XY: 608893 AN XY: 727164

Gnomad4 AFR exome AF: 0.886

Gnomad4 AMR exome AF: 0.903

Gnomad4 ASJ exome AF: 0.768

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.959

Gnomad4 FIN exome AF: 0.883

Gnomad4 NFE exome AF: 0.814

Gnomad4 OTH exome AF: 0.839

GnomAD4 genome AF: 0.857 AC: 130393 AN: 152230 Hom.: 56089 Cov.: 32 AF XY: 0.862 AC XY: 64149 AN XY: 74432

Gnomad4 AFR AF: 0.886

Gnomad4 AMR AF: 0.871

Gnomad4 ASJ AF: 0.768

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.967

Gnomad4 FIN AF: 0.878

Gnomad4 NFE AF: 0.818

Gnomad4 OTH AF: 0.847

Alfa AF: 0.821 Hom.: 122620

Bravo AF: 0.853

TwinsUK AF: 0.808 AC: 2997

ALSPAC AF: 0.821 AC: 3164

ESP6500AA AF: 0.886 AC: 3904

ESP6500EA AF: 0.805 AC: 6923

ExAC AF: 0.868 AC: 105402

Asia WGS AF: 0.976 AC: 3393 AN: 3478

EpiCase AF: 0.808

EpiControl AF: 0.806

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ALPK2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.78
DANN	Benign	0.41
DEOGEN2	Benign	0.0028	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-2.0	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.86	N
REVEL	Benign	0.11
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.0070
MPC		0.079
ClinPred		0.0016	T
GERP RS		2.8
Varity_R		0.016
gMVP		0.12

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

Other links and lift over

dbSNP: rs7240666; hg19: chr18-56149099;