4-112432129-T-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_025144.4(ALPK1):​c.2582T>A​(p.Met861Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M861T) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALPK1 NM_025144.4 missense
• Clinical Significance: Not reported in ClinVar
• 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, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03597477).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALPK1	NM_025144.4	MANE Select	c.2582T>A	p.Met861Lys	missense	Exon 11 of 16	NP_079420.3
	ALPK1	NM_001102406.2		c.2582T>A	p.Met861Lys	missense	Exon 11 of 16	NP_001095876.1
	ALPK1	NM_001253884.2		c.2348T>A	p.Met783Lys	missense	Exon 10 of 15	NP_001240813.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALPK1	ENST00000650871.1	MANE Select	c.2582T>A	p.Met861Lys	missense	Exon 11 of 16	ENSP00000498374.1
	ALPK1	ENST00000177648.13	TSL:1	c.2582T>A	p.Met861Lys	missense	Exon 11 of 16	ENSP00000177648.9
	ALPK1	ENST00000458497.6	TSL:5	c.2582T>A	p.Met861Lys	missense	Exon 12 of 17	ENSP00000398048.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 83

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 160095

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	1.2
DANN	Benign	0.67
DEOGEN2	Benign	0.0010	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.0	N
PhyloP100		-1.3
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.022
Sift	Benign	0.15	T
Sift4G	Benign	0.97	T
Polyphen		0.0	B
Vest4		0.078
MutPred		0.37		Loss of stability (P = 0.001)
MVP		0.10
MPC		0.14
ClinPred		0.13	T
GERP RS		1.7
Varity_R		0.13
Mutation Taster		=99/1	polymorphism

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;