dbSNP rs2074381: ALPK1:p.Asn916Asp (chr4-112432293-A-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_025144.4(ALPK1):c.2746A>G(p.Asn916Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00395 in 1,614,202 control chromosomes in the GnomAD database, including 163 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 0.0062 ( 20 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 143 hom. )

Consequence

ALPK1
NM_025144.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.330

Publications

14 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0021720827).

BP6

Variant 4-112432293-A-G is Benign according to our data. Variant chr4-112432293-A-G is described in ClinVar as Benign. ClinVar VariationId is 2043717.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0641 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ALPK1	NM_025144.4 link	c.2746A>G	p.Asn916Asp	missense_variant	Exon 11 of 16	ENST00000650871.1	NP_079420.3
ALPK1	NM_001102406.2 link	c.2746A>G	p.Asn916Asp	missense_variant	Exon 11 of 16		NP_001095876.1
ALPK1	NM_001253884.2 link	c.2512A>G	p.Asn838Asp	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.2746A>G	p.Asn916Asp	missense_variant	Exon 11 of 16		NM_025144.4	ENSP00000498374.1

Frequencies

GnomAD3 genomes

AF:

0.00620

AC:

943

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.0699

Gnomad SAS

AF:

0.00683

Gnomad FIN

AF:

0.0414

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000970

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00845

AC:

2124

AN:

251300

AF XY:

0.00830

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00308

Gnomad EAS exome

AF:

0.0613

Gnomad FIN exome

AF:

0.0337

Gnomad NFE exome

AF:

0.00103

Gnomad OTH exome

AF:

0.00473

GnomAD4 exome

AF:

0.00371

AC:

5427

AN:

1461890

Hom.:

143

Cov.:

AF XY:

0.00368

AC XY:

2674

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.000358

AC:

AN:

33480

American (AMR)

AF:

0.000291

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00237

AC:

AN:

26136

East Asian (EAS)

AF:

0.0713

AC:

2832

AN:

39696

South Asian (SAS)

AF:

0.00255

AC:

220

AN:

86258

European-Finnish (FIN)

AF:

0.0311

AC:

1659

AN:

53420

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000291

AC:

324

AN:

1112012

Other (OTH)

AF:

0.00495

AC:

299

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

347

694

1040

1387

1734

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<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:

0.00621

AC:

946

AN:

152312

Hom.:

Cov.:

AF XY:

0.00835

AC XY:

622

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.000553

AC:

AN:

41570

American (AMR)

AF:

0.000327

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3466

East Asian (EAS)

AF:

0.0700

AC:

363

AN:

5184

South Asian (SAS)

AF:

0.00663

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0414

AC:

440

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000970

AC:

AN:

68018

Other (OTH)

AF:

0.00473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

100

149

199

249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00172

Hom.:

Bravo

AF:

0.00321

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00783

AC:

951

Asia WGS

AF:

0.0330

AC:

116

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jan 23, 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

0.083

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.42

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.0034

.;T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.54

T;T;.

MetaRNN

Benign

0.0022

T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.5

.;L;L

PhyloP100

-0.33

PrimateAI

Benign

0.28

PROVEAN

Benign

0.060

N;N;N

REVEL

Benign

0.021

Sift

Benign

0.47

T;T;T

Sift4G

Benign

0.55

T;T;T

Polyphen

0.0070

.;B;B

Vest4

0.044

MVP

0.15

MPC

0.099

ClinPred

0.0029

GERP RS

0.32

Varity_R

0.062

Mutation Taster

=99/1

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