4-112423408-A-C

Variant names:

• chr4-112423408-A-C
• rs7658978
• NM_025144.4:c.476-536A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_025144.4(ALPK1):​c.476-536A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.604 in 152,056 control chromosomes in the GnomAD database, including 27,948 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.60 (27948 hom., cov: 32)
• Consequence: ALPK1 NM_025144.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.39
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.777 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.476-536A>C		intron	N/A	NP_079420.3
	ALPK1	NM_001102406.2		c.476-536A>C		intron	N/A	NP_001095876.1	Q96QP1-1
	ALPK1	NM_001253884.2		c.242-536A>C		intron	N/A	NP_001240813.1	Q96QP1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALPK1	ENST00000650871.1	MANE Select	c.476-536A>C		intron	N/A	ENSP00000498374.1	Q96QP1-1
	ALPK1	ENST00000177648.13	TSL:1	c.476-536A>C		intron	N/A	ENSP00000177648.9	Q96QP1-1
	ALPK1	ENST00000909431.1		c.476-536A>C		intron	N/A	ENSP00000579490.1

Frequencies

GnomAD3 genomes AF: 0.603 AC: 91690 AN: 151938 Hom.: 27909 Cov.: 32

Gnomad AFR AF: 0.668

Gnomad AMI AF: 0.442

Gnomad AMR AF: 0.590

Gnomad ASJ AF: 0.568

Gnomad EAS AF: 0.799

Gnomad SAS AF: 0.517

Gnomad FIN AF: 0.586

Gnomad MID AF: 0.563

Gnomad NFE AF: 0.565

Gnomad OTH AF: 0.602

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.604 AC: 91782 AN: 152056 Hom.: 27948 Cov.: 32 AF XY: 0.603 AC XY: 44806 AN XY: 74308

African (AFR) AF: 0.668 AC: 27720 AN: 41476

American (AMR) AF: 0.590 AC: 9017 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.568 AC: 1971 AN: 3470

East Asian (EAS) AF: 0.798 AC: 4123 AN: 5168

South Asian (SAS) AF: 0.517 AC: 2492 AN: 4816

European-Finnish (FIN) AF: 0.586 AC: 6182 AN: 10550

Middle Eastern (MID) AF: 0.558 AC: 164 AN: 294

European-Non Finnish (NFE) AF: 0.565 AC: 38442 AN: 67984

Other (OTH) AF: 0.601 AC: 1269 AN: 2112

Alfa AF: 0.573 Hom.: 33328

Bravo AF: 0.613

Asia WGS AF: 0.611 AC: 2129 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.97
DANN	Benign	0.55
PhyloP100		-1.4
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: rs7658978; hg19: chr4-113344564;