rs2074379

chr4-112431743-G-Achr4-112431743-G-C

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.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. 13/18 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 (32050 hom., cov: 32)
  • Exomes 𝑓: 0.63 (286797 hom.)
• Consequence: ALPK1 NM_025144.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.207

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=3.3397666E-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 id 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/exons	MANE	UniProt
ALPK1	NM_025144.4	c.2196G>A	p.Met732Ile	missense_variant	11/16	ENST00000650871.1
ALPK1	NM_001102406.2	c.2196G>A	p.Met732Ile	missense_variant	11/16
ALPK1	NM_001253884.2	c.1962G>A	p.Met654Ile	missense_variant	10/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALPK1	ENST00000650871.1	c.2196G>A	p.Met732Ile	missense_variant	11/16		NM_025144.4	P1

Frequencies

GnomAD3 genomes AF: 0.648 AC: 98445 AN: 151912 Hom.: 32032 Cov.: 32

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

GnomAD3 exomes AF: 0.616 AC: 154806 AN: 251240 Hom.: 48161 AF XY: 0.613 AC XY: 83314 AN XY: 135804

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 SAS exome AF: 0.551

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.: 70 AF XY: 0.623 AC XY: 453160 AN XY: 727228

Gnomad4 AFR exome AF: 0.709

Gnomad4 AMR exome AF: 0.548

Gnomad4 ASJ exome AF: 0.644

Gnomad4 EAS exome AF: 0.655

Gnomad4 SAS exome AF: 0.552

Gnomad4 FIN exome AF: 0.647

Gnomad4 NFE exome AF: 0.629

Gnomad4 OTH exome AF: 0.627

GnomAD4 genome AF: 0.648 AC: 98520 AN: 152032 Hom.: 32050 Cov.: 32 AF XY: 0.646 AC XY: 48037 AN XY: 74306

Gnomad4 AFR AF: 0.706

Gnomad4 AMR AF: 0.592

Gnomad4 ASJ AF: 0.643

Gnomad4 EAS AF: 0.647

Gnomad4 SAS AF: 0.549

Gnomad4 FIN AF: 0.646

Gnomad4 NFE AF: 0.633

Gnomad4 OTH AF: 0.636

Alfa AF: 0.630 Hom.: 73732

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: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	Jul 14, 2020	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	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	2.4
Dann	Benign	0.49
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.59	T;T;.
MetaRNN	Benign	0.0000033	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.25	T
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	T
GERP RS		3.3
Varity_R		0.087

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: rs2074379; hg19: chr4-113352899; COSMIC: COSV51589168; COSMIC: COSV51589168;