4-112299646-T-C

Variant names:

• chr4-112299646-T-C
• rs6533603
• NM_025144.4:c.-153+2177T>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.-153+2177T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.616 in 152,082 control chromosomes in the GnomAD database, including 30,934 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 0.62 (30934 hom., cov: 32)
• Consequence: ALPK1 NM_025144.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.28
• Publications: 10 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.856 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPK1	NM_025144.4	c.-153+2177T>C		intron_variant	Intron 1 of 15	ENST00000650871.1	NP_079420.3
ALPK1	NM_001102406.2	c.-101+2177T>C		intron_variant	Intron 1 of 15		NP_001095876.1
ALPK1	NM_001253884.2	c.-180+2177T>C		intron_variant	Intron 1 of 14		NP_001240813.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPK1	ENST00000650871.1	c.-153+2177T>C		intron_variant	Intron 1 of 15		NM_025144.4	ENSP00000498374.1

Frequencies

GnomAD3 genomes AF: 0.616 AC: 93570 AN: 151964 Hom.: 30889 Cov.: 32

Gnomad AFR AF: 0.864

Gnomad AMI AF: 0.514

Gnomad AMR AF: 0.630

Gnomad ASJ AF: 0.599

Gnomad EAS AF: 0.714

Gnomad SAS AF: 0.303

Gnomad FIN AF: 0.462

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.502

Gnomad OTH AF: 0.621

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

GnomAD4 genome AF: 0.616 AC: 93662 AN: 152082 Hom.: 30934 Cov.: 32 AF XY: 0.611 AC XY: 45384 AN XY: 74336

African (AFR) AF: 0.864 AC: 35879 AN: 41534

American (AMR) AF: 0.631 AC: 9626 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.599 AC: 2076 AN: 3464

East Asian (EAS) AF: 0.713 AC: 3684 AN: 5164

South Asian (SAS) AF: 0.303 AC: 1460 AN: 4824

European-Finnish (FIN) AF: 0.462 AC: 4882 AN: 10578

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.502 AC: 34101 AN: 67936

Other (OTH) AF: 0.614 AC: 1297 AN: 2112

Alfa AF: 0.539 Hom.: 56118

Bravo AF: 0.647

Asia WGS AF: 0.490 AC: 1706 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.0
DANN	Benign	0.86
PhyloP100		-1.3
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: rs6533603; hg19: chr4-113220802;