chr4-112377832-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_025144.4(ALPK1):​c.55G>A​(p.Asp19Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000285 in 1,613,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

ALPK1
NM_025144.4 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2B:1

Conservation

PhyloP100: 4.10
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.1363154).
BS2
High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ALPK1NM_025144.4 linkuse as main transcriptc.55G>A p.Asp19Asn missense_variant 3/16 ENST00000650871.1 NP_079420.3
ALPK1NM_001102406.2 linkuse as main transcriptc.55G>A p.Asp19Asn missense_variant 3/16 NP_001095876.1
ALPK1NM_001253884.2 linkuse as main transcriptc.-25G>A 5_prime_UTR_variant 3/15 NP_001240813.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ALPK1ENST00000650871.1 linkuse as main transcriptc.55G>A p.Asp19Asn missense_variant 3/16 NM_025144.4 ENSP00000498374 P1Q96QP1-1

Frequencies

GnomAD3 genomes
AF:
0.000138
AC:
21
AN:
152060
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000517
AC:
13
AN:
251244
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135806
show subpopulations
Gnomad AFR exome
AF:
0.000677
Gnomad AMR exome
AF:
0.0000580
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000171
AC:
25
AN:
1461402
Hom.:
0
Cov.:
30
AF XY:
0.0000110
AC XY:
8
AN XY:
726944
show subpopulations
Gnomad4 AFR exome
AF:
0.000568
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.000138
AC:
21
AN:
152178
Hom.:
0
Cov.:
32
AF XY:
0.000134
AC XY:
10
AN XY:
74402
show subpopulations
Gnomad4 AFR
AF:
0.000482
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000772
Hom.:
0
Bravo
AF:
0.000170
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000824
AC:
10

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 23, 2023The c.55G>A (p.D19N) alteration is located in exon 3 (coding exon 1) of the ALPK1 gene. This alteration results from a G to A substitution at nucleotide position 55, causing the aspartic acid (D) at amino acid position 19 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 01, 2023This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 19 of the ALPK1 protein (p.Asp19Asn). This variant is present in population databases (rs199994656, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ALPK1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2074835). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
ALPK1-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesAug 21, 2024This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.50
T
BayesDel_noAF
Benign
-0.58
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.0081
T;T
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Benign
0.75
T;.
M_CAP
Benign
0.017
T
MetaRNN
Benign
0.14
T;T
MetaSVM
Benign
-0.93
T
MutationAssessor
Benign
1.9
L;L
MutationTaster
Benign
1.0
D;N;N
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-1.0
N;N
REVEL
Benign
0.12
Sift
Uncertain
0.015
D;D
Sift4G
Benign
0.16
T;T
Polyphen
1.0
D;D
Vest4
0.36
MVP
0.32
MPC
0.44
ClinPred
0.10
T
GERP RS
5.0
Varity_R
0.29

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199994656; hg19: chr4-113298988; API