chr15-84858223-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020778.5(ALPK3):c.3485G>C(p.Gly1162Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000652 in 1,611,210 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

ALPK3
NM_020778.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 6.82

Variant links:

Genes affected

ALPK3 (HGNC:17574): (alpha kinase 3) Predicted to enable ATP binding activity; protein serine kinase activity; and protein serine/threonine kinase activity. Predicted to be involved in cardiac muscle cell development. Predicted to be active in nucleus. Implicated in hypertrophic cardiomyopathy. [provided by Alliance of Genome Resources, Apr 2022]

ALPK3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPK3	NM_020778.5 link	c.3485G>C	p.Gly1162Ala	missense_variant	Exon 6 of 14	ENST00000258888.6	NP_065829.4	Q96L96

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPK3	ENST00000258888.6 link	c.3485G>C	p.Gly1162Ala	missense_variant	Exon 6 of 14	1	NM_020778.5	ENSP00000258888.6		Q96L96

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000699

AC:

AN:

243178

AF XY:

0.0000682

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000882

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000119

Gnomad OTH exome

AF:

0.000169

GnomAD4 exome

AF:

0.0000658

AC:

AN:

1459138

Hom.:

Cov.:

AF XY:

0.0000565

AC XY:

AN XY:

725674

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33386

American (AMR)

AF:

0.0000675

AC:

AN:

44428

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26042

East Asian (EAS)

AF:

0.00

AC:

AN:

39532

South Asian (SAS)

AF:

0.0000233

AC:

AN:

85752

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53138

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000765

AC:

AN:

1110824

Other (OTH)

AF:

0.0000664

AC:

AN:

60270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74276

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41408

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

67978

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000224

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1364 of the ALPK3 protein (p.Gly1364Ala). This variant is present in population databases (rs752749949, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy (PMID: 30847666, 32480058). ClinVar contains an entry for this variant (Variation ID: 1284767). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ALPK3 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Clinical Genetics, Academic Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 16, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has been reported as a variant of uncertain significance in an individual with ARVC (PMID: 30847666); Has been reported as c.4091 G>C in a male with LVH, who also harbored a c.4997delA likely pathogenic variant in the ALPK3 gene (PMID: 32480058); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.4091G>C; p.(G1364A); This variant is associated with the following publications: (PMID: 33076350, 30847666, 32480058) -

Cardiovascular phenotype

Uncertain:2

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2, BP1 -

Sep 21, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.G1364A variant (also known as c.4091G>C), located in coding exon 6 of the ALPK3 gene, results from a G to C substitution at nucleotide position 4091. The glycine at codon 1364 is replaced by alanine, an amino acid with similar properties. This alteration has been reported in a subject with arrhythmogenic right ventricular cardiomyopathy and co-occurred with an ALPK3 frameshift mutation in an adult with hypertrophic cardiomyopathy (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Herkert JC et al. Am Heart J. 2020 Jul;225:108-119). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Uncertain:1

May 09, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ALPK3 c.3485G>C (p.Gly1162Ala) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 7e-05 in 243178 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ALPK3 causing Cardiomyopathy (7e-05 vs 0.0071), allowing no conclusion about variant significance. c.3485G>C has been observed in individual(s) affected with Cardiomyopathy and Arrhythmogenic right ventricular cardiomyopathy (vanLint_2019, Herkert_2020). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32480058, 30847666). ClinVar contains an entry for this variant (Variation ID: 1284767). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cardiomyopathy, familial hypertrophic 27

Uncertain:1

Jun 29, 2021

Clinical Genomics Laboratory, Stanford Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Gly1364Ala variant has been previously reported in the compound heterozygous statewith a truncating variant (p.Asn1666Thrfs*14) in an adult with hypertrophic cardiomyopathy (Herkert et al., 2020). Additionally, this variant has been reported in the heterozygous state in an individual with arrhythmogenic right ventricular cardiomyopathy with no second variant identified (van Lint et al., 2019).This variant has been identified in 14/124,846 European non-Finnish chromosomes (18/274,450 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency.Computational tools predict that the p.Gly1364Ala is deleterious; however, the accuracy of in silicoalgorithms is limited.These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Gly1364Alavariant is uncertain. Additional information is needed to resolve the significance of this variant.[ACMG evidence codes used: PM2; PM3_Supporting; PP3] -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Benign

-0.034

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.24

MetaRNN

Uncertain

0.45

MetaSVM

Uncertain

0.63

MutationAssessor

Uncertain

2.6

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.51

Sift

Uncertain

0.0010

Sift4G

Benign

0.24

Polyphen

1.0

Vest4

0.46

MVP

0.92

MPC

0.57

ClinPred

0.52

GERP RS

5.8

Varity_R

0.36

gMVP

0.42

Mutation Taster

=72/28

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

chr15-84858223-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over