chr4-112431743-G-C

Variant names:

• chr4-112431743-G-C
• rs2074379
• NM_025144.4:c.2196G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025144.4(ALPK1):​c.2196G>C​(p.Met732Ile) 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALPK1 NM_025144.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.207
• Publications: 39 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07075673).

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.2196G>C	p.Met732Ile	missense	Exon 11 of 16	NP_079420.3
	ALPK1	NM_001102406.2		c.2196G>C	p.Met732Ile	missense	Exon 11 of 16	NP_001095876.1	Q96QP1-1
	ALPK1	NM_001253884.2		c.1962G>C	p.Met654Ile	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.2196G>C	p.Met732Ile	missense	Exon 11 of 16	ENSP00000498374.1	Q96QP1-1
	ALPK1	ENST00000177648.13	TSL:1	c.2196G>C	p.Met732Ile	missense	Exon 11 of 16	ENSP00000177648.9	Q96QP1-1
	ALPK1	ENST00000909431.1		c.2214G>C	p.Met738Ile	missense	Exon 11 of 16	ENSP00000579490.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 70

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.0
DANN	Benign	0.51
DEOGEN2	Benign	0.0018	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.21
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.073
Sift	Benign	0.30	T
Sift4G	Benign	0.69	T
Polyphen		0.0	B
Vest4		0.054
MutPred		0.16		Gain of phosphorylation at T734 (P = 0.0929)
MVP		0.17
MPC		0.096
ClinPred		0.046	T
GERP RS		3.3
Varity_R		0.087
Mutation Taster		=98/2	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: rs2074379; hg19: chr4-113352899;