4-112432129-T-C

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.2582T>C(p.Met861Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.655 in 1,613,994 control chromosomes in the GnomAD database, including 347,307 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M861V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.68 ( 35202 hom., cov: 33)

Exomes 𝑓: 0.65 ( 312105 hom. )

Consequence

ALPK1
NM_025144.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.34

Publications

36 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=1.0688165E-6).

BP6

Variant 4-112432129-T-C is Benign according to our data. Variant chr4-112432129-T-C is described in ClinVar as Benign. ClinVar VariationId is 1280522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.726 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ALPK1	NM_025144.4 link	c.2582T>C	p.Met861Thr	missense_variant	Exon 11 of 16	ENST00000650871.1	NP_079420.3
ALPK1	NM_001102406.2 link	c.2582T>C	p.Met861Thr	missense_variant	Exon 11 of 16		NP_001095876.1
ALPK1	NM_001253884.2 link	c.2348T>C	p.Met783Thr	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.2582T>C	p.Met861Thr	missense_variant	Exon 11 of 16		NM_025144.4	ENSP00000498374.1

Frequencies

GnomAD3 genomes

AF:

0.679

AC:

103184

AN:

152064

Hom.:

35176

Cov.:

show subpopulations

Gnomad AFR

AF:

0.733

Gnomad AMI

AF:

0.754

Gnomad AMR

AF:

0.621

Gnomad ASJ

AF:

0.703

Gnomad EAS

AF:

0.717

Gnomad SAS

AF:

0.569

Gnomad FIN

AF:

0.689

Gnomad MID

AF:

0.633

Gnomad NFE

AF:

0.659

Gnomad OTH

AF:

0.679

GnomAD2 exomes

AF:

0.645

AC:

161810

AN:

250880

AF XY:

0.642

show subpopulations

Gnomad AFR exome

AF:

0.730

Gnomad AMR exome

AF:

0.561

Gnomad ASJ exome

AF:

0.703

Gnomad EAS exome

AF:

0.710

Gnomad FIN exome

AF:

0.685

Gnomad NFE exome

AF:

0.656

Gnomad OTH exome

AF:

0.652

GnomAD4 exome

AF:

0.652

AC:

953092

AN:

1461812

Hom.:

312105

Cov.:

AF XY:

0.650

AC XY:

472492

AN XY:

727198

show subpopulations

African (AFR)

AF:

0.735

AC:

24624

AN:

33480

American (AMR)

AF:

0.571

AC:

25545

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.707

AC:

18472

AN:

26136

East Asian (EAS)

AF:

0.726

AC:

28842

AN:

39700

South Asian (SAS)

AF:

0.567

AC:

48911

AN:

86256

European-Finnish (FIN)

AF:

0.680

AC:

36338

AN:

53414

Middle Eastern (MID)

AF:

0.647

AC:

3734

AN:

5768

European-Non Finnish (NFE)

AF:

0.654

AC:

726904

AN:

1111956

Other (OTH)

AF:

0.658

AC:

39722

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

23281

46563

69844

93126

116407

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19030

38060

57090

76120

95150

<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:

0.679

AC:

103268

AN:

152182

Hom.:

35202

Cov.:

AF XY:

0.678

AC XY:

50405

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.733

AC:

30452

AN:

41522

American (AMR)

AF:

0.621

AC:

9497

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.703

AC:

2440

AN:

3470

East Asian (EAS)

AF:

0.717

AC:

3708

AN:

5170

South Asian (SAS)

AF:

0.568

AC:

2737

AN:

4820

European-Finnish (FIN)

AF:

0.689

AC:

7304

AN:

10604

Middle Eastern (MID)

AF:

0.636

AC:

187

AN:

294

European-Non Finnish (NFE)

AF:

0.659

AC:

44822

AN:

67986

Other (OTH)

AF:

0.678

AC:

1435

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1746

3493

5239

6986

8732

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

816

1632

2448

3264

4080

<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:

0.663

Hom.:

160095

Bravo

AF:

0.678

TwinsUK

AF:

0.644

AC:

2388

ALSPAC

AF:

0.649

AC:

2503

ESP6500AA

AF:

0.725

AC:

3195

ESP6500EA

AF:

0.658

AC:

5658

ExAC

AF:

0.649

AC:

78846

Asia WGS

AF:

0.579

AC:

2014

AN:

3478

EpiCase

AF:

0.661

EpiControl

AF:

0.652

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

- -

Jul 14, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23569188) -

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

0.046

BayesDel_addAF

Benign

-0.85

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.44

(source)

DANN

Benign

0.16

DEOGEN2

Benign

0.00051

.;T;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0032

LIST_S2

Benign

0.23

T;T;.

MetaRNN

Benign

0.0000011

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.1

.;N;N

PhyloP100

-1.3

PrimateAI

Benign

0.29

PROVEAN

Benign

0.55

N;N;N

REVEL

Benign

0.017

Sift

Benign

1.0

T;T;T

Sift4G

Benign

0.64

T;T;T

Polyphen

0.0

.;B;B

Vest4

0.014

MPC

0.099

ClinPred

0.00030

GERP RS

1.7

Varity_R

0.042

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