rs769139957

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_020778.5(ALPK3):c.1417delC(p.Gln473SerfsTer30) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000622 in 1,606,618 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

ALPK3
NM_020778.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: -0.0990

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

hypertrophic cardiomyopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
cardiomyopathy, familial hypertrophic 27
Inheritance: AR, AD, SD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ALPK3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 15-84840690-AC-A is Pathogenic according to our data. Variant chr15-84840690-AC-A is described in ClinVar as Pathogenic. ClinVar VariationId is 427757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPK3	NM_020778.5 link	c.1417delC	p.Gln473SerfsTer30	frameshift_variant	Exon 5 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.1417delC	p.Gln473SerfsTer30	frameshift_variant	Exon 5 of 14	1	NM_020778.5	ENSP00000258888.6		Q96L96

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151786

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000205

AC:

AN:

243794

AF XY:

0.00000760

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000547

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000363

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000619

AC:

AN:

1454832

Hom.:

Cov.:

AF XY:

0.00000691

AC XY:

AN XY:

723264

show subpopulations

African (AFR)

AF:

0.0000301

AC:

AN:

33256

American (AMR)

AF:

0.00

AC:

AN:

43946

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25486

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

84994

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53054

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

0.00000631

AC:

AN:

1108660

Other (OTH)

AF:

0.00

AC:

AN:

60044

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

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151786

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74114

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41306

American (AMR)

AF:

0.00

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67920

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cardiomyopathy

Pathogenic:1

Apr 01, 2016

Caglayan Lab, Istanbul Bilim University

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

not provided

Pathogenic:1

Dec 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Gln675Serfs*30) in the ALPK3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALPK3 are known to be pathogenic (PMID: 21441111, 26846950, 27106955, 34263907). This variant is present in population databases (rs769139957, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with ALPK3-related conditions (PMID: 28630369, 33191771). ClinVar contains an entry for this variant (Variation ID: 427757). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Nov 10, 2021

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2023delC pathogenic mutation, located in coding exon 5 of the ALPK3 gene, results from a deletion of one nucleotide at nucleotide position 2023, causing a translational frameshift with a predicted alternate stop codon (p.Q675Sfs*30). This alteration has been reported as homozygous in two individuals with cardiomyopathy and as compound heterozygous with a missense alteration in ALPK3 in another individual with cardiomyopathy (Çalayan AO et al. Cold Spring Harb Mol Case Stud, 2017 Sep;3:[ePub ahead of print]; Herkert JC et al. Am Heart J, 2020 07;225:108-119). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

ALPK3-related disorder

Pathogenic:1

Aug 26, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ALPK3 c.2023delC variant is predicted to result in a frameshift and premature protein termination (p.Gln675Serfs*30). This variant has been reported in the homozygous and compound heterozygous states in individuals with early-onset cardiomyopathy (Table II and Table SI, Herkert et al. 2020. PubMed ID: 32480058; Çağlayan et al. 2017. PubMed ID: 28630369). In the heterozygous state, this variant was documented in multiple individuals from one family with adult-onset hypertrophic cardiomyopathy in one study (Cheawsamoot et al. 2020. PubMed ID: 33191771), while this variant was also found in apparently unaffected carriers in another study (Çağlayan et al. 2017. PubMed ID: 28630369), suggesting an increased risk with reduced penetrance in the heterozygous state. This variant is reported in 0.0055% of alleles in individuals of East Asian descent in gnomAD. Frameshift variants in ALPK3 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.099

Mutation Taster

=15/185

disease causing (ClinVar)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over