rs2074388

chr4-112431241-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_025144.4(ALPK1):c.1694G>A(p.Gly565Asp) 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 1,613,926 control chromosomes in the GnomAD database, including 318,721 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.65 (32046 hom., cov: 32)
  • Exomes 𝑓: 0.63 (286675 hom.)
• Consequence: ALPK1 NM_025144.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.750

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.4600837E-6).
• BP6: Variant 4-112431241-G-A is Benign according to our data. Variant chr4-112431241-G-A is described in ClinVar as [Benign]. Clinvar id is 1264009.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/exons	MANE	UniProt
ALPK1	NM_025144.4	c.1694G>A	p.Gly565Asp	missense_variant	11/16	ENST00000650871.1
ALPK1	NM_001102406.2	c.1694G>A	p.Gly565Asp	missense_variant	11/16
ALPK1	NM_001253884.2	c.1460G>A	p.Gly487Asp	missense_variant	10/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALPK1	ENST00000650871.1	c.1694G>A	p.Gly565Asp	missense_variant	11/16		NM_025144.4	P1

Frequencies

GnomAD3 genomes AF: 0.648 AC: 98429 AN: 151954 Hom.: 32029 Cov.: 32

Gnomad AFR AF: 0.706

Gnomad AMI AF: 0.660

Gnomad AMR AF: 0.592

Gnomad ASJ AF: 0.643

Gnomad EAS AF: 0.645

Gnomad SAS AF: 0.549

Gnomad FIN AF: 0.646

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.633

Gnomad OTH AF: 0.636

GnomAD3 exomes AF: 0.616 AC: 154781 AN: 251316 Hom.: 48143 AF XY: 0.613 AC XY: 83286 AN XY: 135822

Gnomad AFR exome AF: 0.707

Gnomad AMR exome AF: 0.539

Gnomad ASJ exome AF: 0.639

Gnomad EAS exome AF: 0.648

Gnomad SAS exome AF: 0.550

Gnomad FIN exome AF: 0.649

Gnomad NFE exome AF: 0.631

Gnomad OTH exome AF: 0.611

GnomAD4 exome AF: 0.625 AC: 913734 AN: 1461854 Hom.: 286675 Cov.: 78 AF XY: 0.623 AC XY: 453040 AN XY: 727220

Gnomad4 AFR exome AF: 0.708

Gnomad4 AMR exome AF: 0.548

Gnomad4 ASJ exome AF: 0.644

Gnomad4 EAS exome AF: 0.653

Gnomad4 SAS exome AF: 0.551

Gnomad4 FIN exome AF: 0.647

Gnomad4 NFE exome AF: 0.629

Gnomad4 OTH exome AF: 0.627

GnomAD4 genome AF: 0.648 AC: 98503 AN: 152072 Hom.: 32046 Cov.: 32 AF XY: 0.646 AC XY: 48024 AN XY: 74332

Gnomad4 AFR AF: 0.706

Gnomad4 AMR AF: 0.591

Gnomad4 ASJ AF: 0.643

Gnomad4 EAS AF: 0.645

Gnomad4 SAS AF: 0.548

Gnomad4 FIN AF: 0.646

Gnomad4 NFE AF: 0.633

Gnomad4 OTH AF: 0.634

Alfa AF: 0.631 Hom.: 74815

Bravo AF: 0.647

TwinsUK AF: 0.613 AC: 2272

ALSPAC AF: 0.617 AC: 2377

ESP6500AA AF: 0.700 AC: 3084

ESP6500EA AF: 0.630 AC: 5420

ExAC AF: 0.622 AC: 75514

Asia WGS AF: 0.538 AC: 1870 AN: 3478

EpiCase AF: 0.631

EpiControl AF: 0.622

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 2018	This variant is associated with the following publications: (PMID: 24649057) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	11
Dann	Uncertain	0.99
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.46	T;T;.
MetaRNN	Benign	0.0000035	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.44	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.042	D;D;D
Sift4G	Benign	0.32	T;T;T
Polyphen		0.99	.;D;D
Vest4		0.18
MPC		0.12
ClinPred		0.0051	T
GERP RS		1.8
Varity_R		0.052

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

Other links and lift over

dbSNP: rs2074388; hg19: chr4-113352397;