4-112377851-C-G

Variant names:

• chr4-112377851-C-G
• rs369223684
• NM_025144.4:c.74C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_025144.4(ALPK1):​c.74C>G​(p.Ala25Gly) 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A25V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALPK1 NM_025144.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.57
• Publications: 1 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05023223).
• BP6: Variant 4-112377851-C-G is Benign according to our data. Variant chr4-112377851-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2997485.

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.74C>G	p.Ala25Gly	missense	Exon 3 of 16	NP_079420.3
	ALPK1	NM_001102406.2		c.74C>G	p.Ala25Gly	missense	Exon 3 of 16	NP_001095876.1	Q96QP1-1
	ALPK1	NM_001253884.2		c.-6C>G		5_prime_UTR	Exon 3 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.74C>G	p.Ala25Gly	missense	Exon 3 of 16	ENSP00000498374.1	Q96QP1-1
	ALPK1	ENST00000177648.13	TSL:1	c.74C>G	p.Ala25Gly	missense	Exon 3 of 16	ENSP00000177648.9	Q96QP1-1
	ALPK1	ENST00000909431.1		c.74C>G	p.Ala25Gly	missense	Exon 3 of 16	ENSP00000579490.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	9.5
DANN	Benign	0.67
DEOGEN2	Benign	0.0070	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.6
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.11
Sift	Benign	0.23	T
Sift4G	Uncertain	0.045	D
Polyphen		0.0010	B
Vest4		0.14
MutPred		0.16		Loss of stability (P = 0.054)
MVP		0.23
MPC		0.086
ClinPred		0.047	T
GERP RS		5.0
Varity_R		0.087
Mutation Taster		=92/8	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: rs369223684; hg19: chr4-113299007;