rs11726117

Variant names:

• chr4-112432129-T-C
• rs11726117
• NM_025144.4:c.2582T>C

Your query was ambiguous. Multiple possible variants found:

• chr4-112432129-T-C
• chr4-112432129-T-A

Variant summary

Our verdict is Benign. The variant received -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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M861V) has been classified as Uncertain significance.

• 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
• Publications: 36 publications found

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 Gene-Disease associations (from GenCC):

• retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025144.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALPK1	NM_025144.4	MANE Select	c.2582T>C	p.Met861Thr	missense	Exon 11 of 16	NP_079420.3
	ALPK1	NM_001102406.2		c.2582T>C	p.Met861Thr	missense	Exon 11 of 16	NP_001095876.1	Q96QP1-1
	ALPK1	NM_001253884.2		c.2348T>C	p.Met783Thr	missense	Exon 10 of 15	NP_001240813.1	Q96QP1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALPK1	ENST00000650871.1	MANE Select	c.2582T>C	p.Met861Thr	missense	Exon 11 of 16	ENSP00000498374.1	Q96QP1-1
	ALPK1	ENST00000177648.13	TSL:1	c.2582T>C	p.Met861Thr	missense	Exon 11 of 16	ENSP00000177648.9	Q96QP1-1
	ALPK1	ENST00000909431.1		c.2600T>C	p.Met867Thr	missense	Exon 11 of 16	ENSP00000579490.1

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

GnomAD2 exomes AF: 0.645 AC: 161810 AN: 250880 AF XY: 0.642

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 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

African (AFR) AF: 0.735 AC: 24624 AN: 33480

American (AMR) AF: 0.571 AC: 25545 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.707 AC: 18472 AN: 26136

East Asian (EAS) AF: 0.726 AC: 28842 AN: 39700

South Asian (SAS) AF: 0.567 AC: 48911 AN: 86256

European-Finnish (FIN) AF: 0.680 AC: 36338 AN: 53414

Middle Eastern (MID) AF: 0.647 AC: 3734 AN: 5768

European-Non Finnish (NFE) AF: 0.654 AC: 726904 AN: 1111956

Other (OTH) AF: 0.658 AC: 39722 AN: 60386

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

African (AFR) AF: 0.733 AC: 30452 AN: 41522

American (AMR) AF: 0.621 AC: 9497 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.703 AC: 2440 AN: 3470

East Asian (EAS) AF: 0.717 AC: 3708 AN: 5170

South Asian (SAS) AF: 0.568 AC: 2737 AN: 4820

European-Finnish (FIN) AF: 0.689 AC: 7304 AN: 10604

Middle Eastern (MID) AF: 0.636 AC: 187 AN: 294

European-Non Finnish (NFE) AF: 0.659 AC: 44822 AN: 67986

Other (OTH) AF: 0.678 AC: 1435 AN: 2116

Alfa AF: 0.663 Hom.: 160095

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0032	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.1	N
PhyloP100		-1.3
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.55	N
REVEL	Benign	0.017
Sift	Benign	1.0	T
Sift4G	Benign	0.64	T
Polyphen		0.0	B
Vest4		0.014
MPC		0.099
ClinPred		0.00030	T
GERP RS		1.7
Varity_R		0.042
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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