rs2074388

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_025144.4(ALPK1):c.1694G>A(p.Gly565Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.627 in 1,613,926 control chromosomes in the GnomAD database, including 318,721 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.65 ( 32046 hom., cov: 32)

Exomes 𝑓: 0.63 ( 286675 hom. )

Consequence

ALPK1
NM_025144.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.750

Publications

39 publications found

Variant links:

Genes affected

ALPK1 (HGNC:20917): (alpha kinase 1) This gene encodes an alpha kinase. Mice which were homozygous for disrupted copies of this gene exhibited coordination defects (PMID: 21208416). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

ALPK1 Gene-Disease associations (from GenCC):

retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ALPK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.4600837E-6).

BP6

Variant 4-112431241-G-A is Benign according to our data. Variant chr4-112431241-G-A is described in ClinVar as Benign. ClinVar VariationId is 1264009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.699 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ALPK1	NM_025144.4 link	c.1694G>A	p.Gly565Asp	missense_variant	Exon 11 of 16	ENST00000650871.1	NP_079420.3
ALPK1	NM_001102406.2 link	c.1694G>A	p.Gly565Asp	missense_variant	Exon 11 of 16		NP_001095876.1
ALPK1	NM_001253884.2 link	c.1460G>A	p.Gly487Asp	missense_variant	Exon 10 of 15		NP_001240813.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPK1	ENST00000650871.1 link	c.1694G>A	p.Gly565Asp	missense_variant	Exon 11 of 16		NM_025144.4	ENSP00000498374.1

Frequencies

GnomAD3 genomes

AF:

0.648

AC:

98429

AN:

151954

Hom.:

32029

Cov.:

show subpopulations

Gnomad AFR

AF:

0.706

Gnomad AMI

AF:

0.660

Gnomad AMR

AF:

0.592

Gnomad ASJ

AF:

0.643

Gnomad EAS

AF:

0.645

Gnomad SAS

AF:

0.549

Gnomad FIN

AF:

0.646

Gnomad MID

AF:

0.579

Gnomad NFE

AF:

0.633

Gnomad OTH

AF:

0.636

GnomAD2 exomes

AF:

0.616

AC:

154781

AN:

251316

AF XY:

0.613

show subpopulations

Gnomad AFR exome

AF:

0.707

Gnomad AMR exome

AF:

0.539

Gnomad ASJ exome

AF:

0.639

Gnomad EAS exome

AF:

0.648

Gnomad FIN exome

AF:

0.649

Gnomad NFE exome

AF:

0.631

Gnomad OTH exome

AF:

0.611

GnomAD4 exome

AF:

0.625

AC:

913734

AN:

1461854

Hom.:

286675

Cov.:

AF XY:

0.623

AC XY:

453040

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.708

AC:

23711

AN:

33480

American (AMR)

AF:

0.548

AC:

24487

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.644

AC:

16825

AN:

26136

East Asian (EAS)

AF:

0.653

AC:

25931

AN:

39698

South Asian (SAS)

AF:

0.551

AC:

47541

AN:

86256

European-Finnish (FIN)

AF:

0.647

AC:

34545

AN:

53410

Middle Eastern (MID)

AF:

0.604

AC:

3483

AN:

5768

European-Non Finnish (NFE)

AF:

0.629

AC:

699357

AN:

1111992

Other (OTH)

AF:

0.627

AC:

37854

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

23973

47946

71920

95893

119866

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18644

37288

55932

74576

93220

<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:

0.648

AC:

98503

AN:

152072

Hom.:

32046

Cov.:

AF XY:

0.646

AC XY:

48024

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.706

AC:

29275

AN:

41472

American (AMR)

AF:

0.591

AC:

9037

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.643

AC:

2234

AN:

3472

East Asian (EAS)

AF:

0.645

AC:

3326

AN:

5156

South Asian (SAS)

AF:

0.548

AC:

2638

AN:

4816

European-Finnish (FIN)

AF:

0.646

AC:

6832

AN:

10584

Middle Eastern (MID)

AF:

0.582

AC:

171

AN:

294

European-Non Finnish (NFE)

AF:

0.633

AC:

43048

AN:

67972

Other (OTH)

AF:

0.634

AC:

1340

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1792

3584

5376

7168

8960

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

798

1596

2394

3192

3990

<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:

0.634

Hom.:

105514

Bravo

AF:

0.647

TwinsUK

AF:

0.613

AC:

2272

ALSPAC

AF:

0.617

AC:

2377

ESP6500AA

AF:

0.700

AC:

3084

ESP6500EA

AF:

0.630

AC:

5420

ExAC

AF:

0.622

AC:

75514

Asia WGS

AF:

0.538

AC:

1870

AN:

3478

EpiCase

AF:

0.631

EpiControl

AF:

0.622

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Aug 02, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24649057)

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0

.;T;T

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.090

LIST_S2

Benign

0.46

T;T;.

MetaRNN

Benign

0.0000035

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

.;M;M

PhyloP100

0.75

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.44

N;N;N

REVEL

Benign

0.14

Sift

Benign

0.042

D;D;D

Sift4G

Benign

0.32

T;T;T

Vest4

0.18

ClinPred

0.0051

GERP RS

1.8

Varity_R

0.052

Mutation Taster

=100/0

polymorphism (auto)

(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