rs747393894

Variant names:

• chr4-112377863-C-A
• rs747393894
• NM_025144.4:c.86C>A

Your query was ambiguous. Multiple possible variants found:

• chr4-112377863-C-A
• chr4-112377863-C-T

Variant summary

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

The NM_025144.4(ALPK1):​c.86C>A​(p.Ser29*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S29S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ALPK1 NM_025144.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.892
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.86C>A	p.Ser29*	stop_gained	Exon 3 of 16	NP_079420.3
	ALPK1	NM_001102406.2		c.86C>A	p.Ser29*	stop_gained	Exon 3 of 16	NP_001095876.1	Q96QP1-1
	ALPK1	NM_001253884.2		c.7C>A	p.Arg3Arg	synonymous	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.86C>A	p.Ser29*	stop_gained	Exon 3 of 16	ENSP00000498374.1	Q96QP1-1
	ALPK1	ENST00000177648.13	TSL:1	c.86C>A	p.Ser29*	stop_gained	Exon 3 of 16	ENSP00000177648.9	Q96QP1-1
	ALPK1	ENST00000909431.1		c.86C>A	p.Ser29*	stop_gained	Exon 3 of 16	ENSP00000579490.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461166 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726772

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111532

Other (OTH) AF: 0.00 AC: 0 AN: 60378

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Benign	0.18
Eigen_PC	Benign	-0.098
FATHMM_MKL	Benign	0.064	N
PhyloP100		0.89
Vest4		0.32
GERP RS		3.0
Mutation Taster		=4/196	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs747393894; hg19: chr4-113299019;