NM_025144.4:c.2196G>A

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.2196G>A(p.Met732Ile) 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 1,613,900 control chromosomes in the GnomAD database, including 318,847 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 (★★).

Frequency

Genomes: 𝑓 0.65 ( 32050 hom., cov: 32)

Exomes 𝑓: 0.63 ( 286797 hom. )

Consequence

ALPK1
NM_025144.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.207

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=3.3397666E-6).

BP6

Variant 4-112431743-G-A is Benign according to our data. Variant chr4-112431743-G-A is described in ClinVar as Benign. ClinVar VariationId is 1247351.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	UniProt
ALPK1	NM_025144.4 link	c.2196G>A	p.Met732Ile	missense_variant	Exon 11 of 16	ENST00000650871.1	NP_079420.3	Q96QP1-1
ALPK1	NM_001102406.2 link	c.2196G>A	p.Met732Ile	missense_variant	Exon 11 of 16		NP_001095876.1	Q96QP1-1
ALPK1	NM_001253884.2 link	c.1962G>A	p.Met654Ile	missense_variant	Exon 10 of 15		NP_001240813.1	Q96QP1-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPK1	ENST00000650871.1 link	c.2196G>A	p.Met732Ile	missense_variant	Exon 11 of 16		NM_025144.4	ENSP00000498374.1		Q96QP1-1

Frequencies

GnomAD3 genomes

AF:

0.648

AC:

98445

AN:

151912

Hom.:

32032

Cov.:

show subpopulations

Gnomad AFR

AF:

0.706

Gnomad AMI

AF:

0.661

Gnomad AMR

AF:

0.593

Gnomad ASJ

AF:

0.643

Gnomad EAS

AF:

0.648

Gnomad SAS

AF:

0.550

Gnomad FIN

AF:

0.646

Gnomad MID

AF:

0.582

Gnomad NFE

AF:

0.633

Gnomad OTH

AF:

0.638

GnomAD2 exomes

AF:

0.616

AC:

154806

AN:

251240

AF XY:

0.613

show subpopulations

Gnomad AFR exome

AF:

0.706

Gnomad AMR exome

AF:

0.539

Gnomad ASJ exome

AF:

0.639

Gnomad EAS exome

AF:

0.649

Gnomad FIN exome

AF:

0.649

Gnomad NFE exome

AF:

0.631

Gnomad OTH exome

AF:

0.611

GnomAD4 exome

AF:

0.625

AC:

913934

AN:

1461868

Hom.:

286797

Cov.:

AF XY:

0.623

AC XY:

453160

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.709

AC:

23720

AN:

33478

American (AMR)

AF:

0.548

AC:

24498

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.644

AC:

16827

AN:

26136

East Asian (EAS)

AF:

0.655

AC:

25989

AN:

39700

South Asian (SAS)

AF:

0.552

AC:

47617

AN:

86258

European-Finnish (FIN)

AF:

0.647

AC:

34549

AN:

53414

Middle Eastern (MID)

AF:

0.604

AC:

3482

AN:

5768

European-Non Finnish (NFE)

AF:

0.629

AC:

699383

AN:

1112000

Other (OTH)

AF:

0.627

AC:

37869

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

23243

46486

69728

92971

116214

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18646

37292

55938

74584

93230

<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:

98520

AN:

152032

Hom.:

32050

Cov.:

AF XY:

0.646

AC XY:

48037

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.706

AC:

29288

AN:

41470

American (AMR)

AF:

0.592

AC:

9041

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.643

AC:

2230

AN:

3468

East Asian (EAS)

AF:

0.647

AC:

3340

AN:

5162

South Asian (SAS)

AF:

0.549

AC:

2643

AN:

4818

European-Finnish (FIN)

AF:

0.646

AC:

6821

AN:

10556

Middle Eastern (MID)

AF:

0.585

AC:

172

AN:

294

European-Non Finnish (NFE)

AF:

0.633

AC:

43042

AN:

67984

Other (OTH)

AF:

0.636

AC:

1340

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1798

3596

5395

7193

8991

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.:

104412

Bravo

AF:

0.647

TwinsUK

AF:

0.614

AC:

2275

ALSPAC

AF:

0.617

AC:

2378

ESP6500AA

AF:

0.700

AC:

3083

ESP6500EA

AF:

0.630

AC:

5420

ExAC

AF:

0.622

AC:

75540

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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: 24649057) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

2.4

(source)

DANN

Benign

0.49

DEOGEN2

Benign

0.0018

.;T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.59

T;T;.

MetaRNN

Benign

0.0000033

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

.;N;N

PhyloP100

0.21

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.090

N;N;N

REVEL

Benign

0.076

Sift

Benign

0.30

T;T;T

Sift4G

Benign

0.69

T;T;T

Polyphen

0.0

.;B;B

Vest4

0.054

MutPred

0.16

.;Gain of phosphorylation at T734 (P = 0.0929);Gain of phosphorylation at T734 (P = 0.0929);

MPC

0.096

ClinPred

0.011

GERP RS

3.3

Varity_R

0.087

Mutation Taster

=98/2

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