4-112432129-T-C

Position:

• chr4-112432129-T-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.2582T>C​(p.Met861Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.655 in 1,613,994 control chromosomes in the GnomAD database, including 347,307 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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 0.68 (35202 hom., cov: 33)
  • Exomes 𝑓: 0.65 (312105 hom.)
• Consequence: ALPK1 NM_025144.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.34

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0688165E-6).
• BP6: Variant 4-112432129-T-C is Benign according to our data. Variant chr4-112432129-T-C is described in ClinVar as [Benign]. Clinvar id is 1280522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.726 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALPK1	NM_025144.4	c.2582T>C	p.Met861Thr	missense_variant	11/16	ENST00000650871.1	NP_079420.3
ALPK1	NM_001102406.2	c.2582T>C	p.Met861Thr	missense_variant	11/16		NP_001095876.1
ALPK1	NM_001253884.2	c.2348T>C	p.Met783Thr	missense_variant	10/15		NP_001240813.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALPK1	ENST00000650871.1	c.2582T>C	p.Met861Thr	missense_variant	11/16		NM_025144.4	ENSP00000498374.1

Frequencies

GnomAD3 genomes AF: 0.679 AC: 103184 AN: 152064 Hom.: 35176 Cov.: 33

Gnomad AFR AF: 0.733

Gnomad AMI AF: 0.754

Gnomad AMR AF: 0.621

Gnomad ASJ AF: 0.703

Gnomad EAS AF: 0.717

Gnomad SAS AF: 0.569

Gnomad FIN AF: 0.689

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.659

Gnomad OTH AF: 0.679

GnomAD3 exomes AF: 0.645 AC: 161810 AN: 250880 Hom.: 52722 AF XY: 0.642 AC XY: 87104 AN XY: 135586

Gnomad AFR exome AF: 0.730

Gnomad AMR exome AF: 0.561

Gnomad ASJ exome AF: 0.703

Gnomad EAS exome AF: 0.710

Gnomad SAS exome AF: 0.565

Gnomad FIN exome AF: 0.685

Gnomad NFE exome AF: 0.656

Gnomad OTH exome AF: 0.652

GnomAD4 exome AF: 0.652 AC: 953092 AN: 1461812 Hom.: 312105 Cov.: 83 AF XY: 0.650 AC XY: 472492 AN XY: 727198

Gnomad4 AFR exome AF: 0.735

Gnomad4 AMR exome AF: 0.571

Gnomad4 ASJ exome AF: 0.707

Gnomad4 EAS exome AF: 0.726

Gnomad4 SAS exome AF: 0.567

Gnomad4 FIN exome AF: 0.680

Gnomad4 NFE exome AF: 0.654

Gnomad4 OTH exome AF: 0.658

GnomAD4 genome AF: 0.679 AC: 103268 AN: 152182 Hom.: 35202 Cov.: 33 AF XY: 0.678 AC XY: 50405 AN XY: 74396

Gnomad4 AFR AF: 0.733

Gnomad4 AMR AF: 0.621

Gnomad4 ASJ AF: 0.703

Gnomad4 EAS AF: 0.717

Gnomad4 SAS AF: 0.568

Gnomad4 FIN AF: 0.689

Gnomad4 NFE AF: 0.659

Gnomad4 OTH AF: 0.678

Alfa AF: 0.659 Hom.: 85083

Bravo AF: 0.678

TwinsUK AF: 0.644 AC: 2388

ALSPAC AF: 0.649 AC: 2503

ESP6500AA AF: 0.725 AC: 3195

ESP6500EA AF: 0.658 AC: 5658

ExAC AF: 0.649 AC: 78846

Asia WGS AF: 0.579 AC: 2014 AN: 3478

EpiCase AF: 0.661

EpiControl AF: 0.652

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2020	This variant is associated with the following publications: (PMID: 23569188) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.44
DANN	Benign	0.16
DEOGEN2	Benign	0.00051	.;T;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0032	N
LIST_S2	Benign	0.23	T;T;.
MetaRNN	Benign	0.0000011	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.1	.;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.55	N;N;N
REVEL	Benign	0.017
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.64	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.014
MPC		0.099
ClinPred		0.00030	T
GERP RS		1.7
Varity_R		0.042

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: rs11726117; hg19: chr4-113353285; COSMIC: COSV51589327; COSMIC: COSV51589327;