15-84827366-C-G

Variant names:

• chr15-84827366-C-G
• rs891286
• NM_020778.5:c.183-118C>G

Variant summary

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

The NM_020778.5(ALPK3):​c.183-118C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.808 in 1,436,426 control chromosomes in the GnomAD database, including 470,265 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (54301 hom., cov: 34)
  • Exomes 𝑓: 0.80 (415964 hom.)
• Consequence: ALPK3 NM_020778.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.553
• Publications: 8 publications found

Genes affected

ALPK3 (HGNC:17574): (alpha kinase 3) Predicted to enable ATP binding activity; protein serine kinase activity; and protein serine/threonine kinase activity. Predicted to be involved in cardiac muscle cell development. Predicted to be active in nucleus. Implicated in hypertrophic cardiomyopathy. [provided by Alliance of Genome Resources, Apr 2022]

ALPK3 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• cardiomyopathy, familial hypertrophic 27

  Inheritance: AR, AD, SD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 15-84827366-C-G is Benign according to our data. Variant chr15-84827366-C-G is described in ClinVar as Benign. ClinVar VariationId is 678441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.942 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020778.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALPK3	NM_020778.5	MANE Select	c.183-118C>G		intron	N/A	NP_065829.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALPK3	ENST00000258888.6	TSL:1 MANE Select	c.183-118C>G		intron	N/A	ENSP00000258888.6

Frequencies

GnomAD3 genomes AF: 0.841 AC: 127977 AN: 152142 Hom.: 54250 Cov.: 34

Gnomad AFR AF: 0.950

Gnomad AMI AF: 0.820

Gnomad AMR AF: 0.754

Gnomad ASJ AF: 0.855

Gnomad EAS AF: 0.944

Gnomad SAS AF: 0.789

Gnomad FIN AF: 0.755

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.804

Gnomad OTH AF: 0.823

GnomAD4 exome AF: 0.804 AC: 1031902 AN: 1284166 Hom.: 415964 AF XY: 0.803 AC XY: 511749 AN XY: 637328

African (AFR) AF: 0.957 AC: 28552 AN: 29850

American (AMR) AF: 0.742 AC: 28734 AN: 38750

Ashkenazi Jewish (ASJ) AF: 0.848 AC: 18592 AN: 21918

East Asian (EAS) AF: 0.948 AC: 36432 AN: 38440

South Asian (SAS) AF: 0.794 AC: 59006 AN: 74294

European-Finnish (FIN) AF: 0.763 AC: 30571 AN: 40070

Middle Eastern (MID) AF: 0.792 AC: 3056 AN: 3858

European-Non Finnish (NFE) AF: 0.796 AC: 782949 AN: 983044

Other (OTH) AF: 0.816 AC: 44010 AN: 53942

GnomAD4 genome AF: 0.841 AC: 128081 AN: 152260 Hom.: 54301 Cov.: 34 AF XY: 0.837 AC XY: 62322 AN XY: 74442

African (AFR) AF: 0.950 AC: 39500 AN: 41572

American (AMR) AF: 0.753 AC: 11516 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.855 AC: 2969 AN: 3472

East Asian (EAS) AF: 0.944 AC: 4890 AN: 5182

South Asian (SAS) AF: 0.790 AC: 3808 AN: 4822

European-Finnish (FIN) AF: 0.755 AC: 8004 AN: 10596

Middle Eastern (MID) AF: 0.827 AC: 243 AN: 294

European-Non Finnish (NFE) AF: 0.804 AC: 54671 AN: 68002

Other (OTH) AF: 0.819 AC: 1734 AN: 2116

Alfa AF: 0.832 Hom.: 6565

Bravo AF: 0.846

Asia WGS AF: 0.866 AC: 3013 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	9.6
DANN	Benign	0.63
PhyloP100		0.55
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: rs891286; hg19: chr15-85370597;