chr18-58481867-T-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_052947.4(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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2157M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.86 (56089 hom., cov: 32)
  • Exomes 𝑓: 0.83 (510664 hom.)
• Consequence: ALPK2 NM_052947.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• 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: Benign. The variant received -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 VariationId is 3060101.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

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>G	p.Ile2157Val	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>G	p.Ile2157Val	missense	Exon 13 of 13	ENSP00000354991.3	Q86TB3
	ALPK2	ENST00000941324.1		c.6433A>G	p.Ile2145Val	missense	Exon 12 of 12	ENSP00000611383.1
	ALPK2	ENST00000857519.1		c.3376A>G	p.Ile1126Val	missense	Exon 13 of 13	ENSP00000527578.1

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

GnomAD2 exomes AF: 0.868 AC: 218192 AN: 251312 AF XY: 0.868

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 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

African (AFR) AF: 0.886 AC: 29668 AN: 33480

American (AMR) AF: 0.903 AC: 40392 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.768 AC: 20064 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39685 AN: 39700

South Asian (SAS) AF: 0.959 AC: 82694 AN: 86256

European-Finnish (FIN) AF: 0.883 AC: 47158 AN: 53420

Middle Eastern (MID) AF: 0.832 AC: 4799 AN: 5768

European-Non Finnish (NFE) AF: 0.814 AC: 904556 AN: 1111860

Other (OTH) AF: 0.839 AC: 50685 AN: 60394

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

African (AFR) AF: 0.886 AC: 36794 AN: 41530

American (AMR) AF: 0.871 AC: 13318 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.768 AC: 2664 AN: 3468

East Asian (EAS) AF: 0.999 AC: 5183 AN: 5188

South Asian (SAS) AF: 0.967 AC: 4667 AN: 4826

European-Finnish (FIN) AF: 0.878 AC: 9308 AN: 10604

Middle Eastern (MID) AF: 0.803 AC: 236 AN: 294

European-Non Finnish (NFE) AF: 0.818 AC: 55640 AN: 68012

Other (OTH) AF: 0.847 AC: 1789 AN: 2112

Alfa AF: 0.827 Hom.: 172625

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

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	ALPK2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.49
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
Mutation Taster		=100/0	polymorphism (auto)

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; COSMIC: COSV104675079; COSMIC: COSV104675079;