4-112441466-C-G

Variant names:

• chr4-112441466-C-G
• rs231253
• NM_025144.4:c.*256C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_025144.4(ALPK1):​c.*256C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.665 in 540,514 control chromosomes in the GnomAD database, including 120,186 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (35184 hom., cov: 32)
  • Exomes 𝑓: 0.66 (85002 hom.)
• Consequence: ALPK1 NM_025144.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0540
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 4-112441466-C-G is Benign according to our data. Variant chr4-112441466-C-G is described in ClinVar as Benign. ClinVar VariationId is 1236964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.728 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPK1	NM_025144.4	c.*256C>G		3_prime_UTR_variant	Exon 16 of 16	ENST00000650871.1	NP_079420.3
ALPK1	NM_001102406.2	c.*256C>G		3_prime_UTR_variant	Exon 16 of 16		NP_001095876.1
ALPK1	NM_001253884.2	c.*256C>G		3_prime_UTR_variant	Exon 15 of 15		NP_001240813.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPK1	ENST00000650871.1	c.*256C>G		3_prime_UTR_variant	Exon 16 of 16		NM_025144.4	ENSP00000498374.1

Frequencies

GnomAD3 genomes AF: 0.679 AC: 103152 AN: 151990 Hom.: 35162 Cov.: 32

Gnomad AFR AF: 0.735

Gnomad AMI AF: 0.752

Gnomad AMR AF: 0.618

Gnomad ASJ AF: 0.702

Gnomad EAS AF: 0.723

Gnomad SAS AF: 0.578

Gnomad FIN AF: 0.691

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.658

Gnomad OTH AF: 0.677

GnomAD4 exome AF: 0.660 AC: 256177 AN: 388406 Hom.: 85002 Cov.: 2 AF XY: 0.655 AC XY: 133371 AN XY: 203566

African (AFR) AF: 0.734 AC: 8327 AN: 11344

American (AMR) AF: 0.598 AC: 9086 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.713 AC: 8751 AN: 12278

East Asian (EAS) AF: 0.736 AC: 20790 AN: 28258

South Asian (SAS) AF: 0.581 AC: 20877 AN: 35944

European-Finnish (FIN) AF: 0.681 AC: 17580 AN: 25830

Middle Eastern (MID) AF: 0.633 AC: 1091 AN: 1724

European-Non Finnish (NFE) AF: 0.658 AC: 154537 AN: 234906

Other (OTH) AF: 0.660 AC: 15138 AN: 22922

GnomAD4 genome AF: 0.679 AC: 103227 AN: 152108 Hom.: 35184 Cov.: 32 AF XY: 0.678 AC XY: 50388 AN XY: 74352

African (AFR) AF: 0.735 AC: 30507 AN: 41486

American (AMR) AF: 0.618 AC: 9440 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.702 AC: 2434 AN: 3468

East Asian (EAS) AF: 0.723 AC: 3731 AN: 5160

South Asian (SAS) AF: 0.576 AC: 2779 AN: 4824

European-Finnish (FIN) AF: 0.691 AC: 7310 AN: 10574

Middle Eastern (MID) AF: 0.626 AC: 184 AN: 294

European-Non Finnish (NFE) AF: 0.658 AC: 44725 AN: 67996

Other (OTH) AF: 0.676 AC: 1431 AN: 2116

Alfa AF: 0.675 Hom.: 4084

Bravo AF: 0.677

Asia WGS AF: 0.587 AC: 2045 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 14, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23569188) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.3
DANN	Benign	0.68
PhyloP100		-0.054
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: rs231253; hg19: chr4-113362622;