rs2074381

chr4-112432293-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_025144.4(ALPK1):c.2746A>G(p.Asn916Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00395 in 1,614,202 control chromosomes in the GnomAD database, including 163 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 0.0062 (20 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (143 hom.)
• Consequence: ALPK1 NM_025144.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.330

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021720827).
• BP6: Variant 4-112432293-A-G is Benign according to our data. Variant chr4-112432293-A-G is described in ClinVar as [Benign]. Clinvar id is 2043717.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0641 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALPK1	NM_025144.4	c.2746A>G	p.Asn916Asp	missense_variant	11/16	ENST00000650871.1
ALPK1	NM_001102406.2	c.2746A>G	p.Asn916Asp	missense_variant	11/16
ALPK1	NM_001253884.2	c.2512A>G	p.Asn838Asp	missense_variant	10/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALPK1	ENST00000650871.1	c.2746A>G	p.Asn916Asp	missense_variant	11/16		NM_025144.4	P1

Frequencies

GnomAD3 genomes AF: 0.00620 AC: 943 AN: 152194 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.0699

Gnomad SAS AF: 0.00683

Gnomad FIN AF: 0.0414

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00845 AC: 2124 AN: 251300 Hom.: 48 AF XY: 0.00830 AC XY: 1127 AN XY: 135804

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.0613

Gnomad SAS exome AF: 0.00235

Gnomad FIN exome AF: 0.0337

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00371 AC: 5427 AN: 1461890 Hom.: 143 Cov.: 35 AF XY: 0.00368 AC XY: 2674 AN XY: 727244

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00237

Gnomad4 EAS exome AF: 0.0713

Gnomad4 SAS exome AF: 0.00255

Gnomad4 FIN exome AF: 0.0311

Gnomad4 NFE exome AF: 0.000291

Gnomad4 OTH exome AF: 0.00495

GnomAD4 genome AF: 0.00621 AC: 946 AN: 152312 Hom.: 20 Cov.: 32 AF XY: 0.00835 AC XY: 622 AN XY: 74472

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.0700

Gnomad4 SAS AF: 0.00663

Gnomad4 FIN AF: 0.0414

Gnomad4 NFE AF: 0.000970

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00177 Hom.: 11

Bravo AF: 0.00321

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00783 AC: 951

Asia WGS AF: 0.0330 AC: 116 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.42
Dann	Benign	0.96
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.54	T;T;.
MetaRNN	Benign	0.0022	T;T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.060	N;N;N
REVEL	Benign	0.021
Sift	Benign	0.47	T;T;T
Sift4G	Benign	0.55	T;T;T
Polyphen		0.0070	.;B;B
Vest4		0.044
MVP		0.15
MPC		0.099
ClinPred		0.0029	T
GERP RS		0.32
Varity_R		0.062

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: rs2074381; hg19: chr4-113353449; COSMIC: COSV51585735; COSMIC: COSV51585735;