chr18-58481867-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The ENST00000361673.4(ALPK2):ā€‹c.6469A>Gā€‹(p.Ile2157Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.837 in 1,613,966 control chromosomes in the GnomAD database, including 566,753 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2157K) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.86 ( 56089 hom., cov: 32)
Exomes š‘“: 0.83 ( 510664 hom. )

Consequence

ALPK2
ENST00000361673.4 missense

Scores

18

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.491
Variant links:
Genes affected
ALPK2 (HGNC:20565): (alpha kinase 2) Predicted to enable ATP binding activity; protein serine kinase activity; and protein serine/threonine kinase activity. Involved in several processes, including epicardium morphogenesis; heart development; and negative regulation of Wnt signaling pathway involved in heart development. Acts upstream of or within regulation of gene expression. Colocalizes with basolateral plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=1.2549042E-6).
BP6
Variant 18-58481867-T-C is Benign according to our data. Variant chr18-58481867-T-C is described in ClinVar as [Benign]. Clinvar id is 3060101.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr18-58481867-T-C is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ALPK2NM_052947.4 linkuse as main transcriptc.6469A>G p.Ile2157Val missense_variant 13/13 ENST00000361673.4 NP_443179.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ALPK2ENST00000361673.4 linkuse as main transcriptc.6469A>G p.Ile2157Val missense_variant 13/131 NM_052947.4 ENSP00000354991 P1

Frequencies

GnomAD3 genomes
AF:
0.856
AC:
130272
AN:
152112
Hom.:
56028
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.886
Gnomad AMI
AF:
0.873
Gnomad AMR
AF:
0.871
Gnomad ASJ
AF:
0.768
Gnomad EAS
AF:
0.999
Gnomad SAS
AF:
0.968
Gnomad FIN
AF:
0.878
Gnomad MID
AF:
0.794
Gnomad NFE
AF:
0.818
Gnomad OTH
AF:
0.846
GnomAD3 exomes
AF:
0.868
AC:
218192
AN:
251312
Hom.:
95300
AF XY:
0.868
AC XY:
117892
AN XY:
135826
show subpopulations
Gnomad AFR exome
AF:
0.884
Gnomad AMR exome
AF:
0.908
Gnomad ASJ exome
AF:
0.768
Gnomad EAS exome
AF:
1.00
Gnomad SAS exome
AF:
0.962
Gnomad FIN exome
AF:
0.882
Gnomad NFE exome
AF:
0.815
Gnomad OTH exome
AF:
0.845
GnomAD4 exome
AF:
0.834
AC:
1219701
AN:
1461736
Hom.:
510664
Cov.:
61
AF XY:
0.837
AC XY:
608893
AN XY:
727164
show subpopulations
Gnomad4 AFR exome
AF:
0.886
Gnomad4 AMR exome
AF:
0.903
Gnomad4 ASJ exome
AF:
0.768
Gnomad4 EAS exome
AF:
1.00
Gnomad4 SAS exome
AF:
0.959
Gnomad4 FIN exome
AF:
0.883
Gnomad4 NFE exome
AF:
0.814
Gnomad4 OTH exome
AF:
0.839
GnomAD4 genome
AF:
0.857
AC:
130393
AN:
152230
Hom.:
56089
Cov.:
32
AF XY:
0.862
AC XY:
64149
AN XY:
74432
show subpopulations
Gnomad4 AFR
AF:
0.886
Gnomad4 AMR
AF:
0.871
Gnomad4 ASJ
AF:
0.768
Gnomad4 EAS
AF:
0.999
Gnomad4 SAS
AF:
0.967
Gnomad4 FIN
AF:
0.878
Gnomad4 NFE
AF:
0.818
Gnomad4 OTH
AF:
0.847
Alfa
AF:
0.821
Hom.:
122620
Bravo
AF:
0.853
TwinsUK
AF:
0.808
AC:
2997
ALSPAC
AF:
0.821
AC:
3164
ESP6500AA
AF:
0.886
AC:
3904
ESP6500EA
AF:
0.805
AC:
6923
ExAC
AF:
0.868
AC:
105402
Asia WGS
AF:
0.976
AC:
3393
AN:
3478
EpiCase
AF:
0.808
EpiControl
AF:
0.806

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

ALPK2-related disorder Benign:1
Benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesOct 17, 2019This variant is classified as 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
0.063
BayesDel_addAF
Benign
-0.81
T
BayesDel_noAF
Benign
-0.79
CADD
Benign
0.78
DANN
Benign
0.41
DEOGEN2
Benign
0.0028
T
Eigen
Benign
-1.6
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.014
N
LIST_S2
Benign
0.12
T
MetaRNN
Benign
0.0000013
T
MetaSVM
Benign
-0.92
T
MutationAssessor
Benign
-2.0
N
MutationTaster
Benign
1.0
P
PrimateAI
Benign
0.27
T
PROVEAN
Benign
0.86
N
REVEL
Benign
0.11
Sift
Benign
1.0
T
Sift4G
Benign
1.0
T
Polyphen
0.0
B
Vest4
0.0070
MPC
0.079
ClinPred
0.0016
T
GERP RS
2.8
Varity_R
0.016
gMVP
0.12

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: rs7240666; hg19: chr18-56149099; API