NM_020778.5:c.3628C>T

Variant names:

• chr15-84858366-C-T
• rs55752937
• NM_020778.5:c.3628C>T

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.3628C>T​(p.Arg1210Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,554,078 control chromosomes in the GnomAD database, including 229 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1210Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.022 (92 hom., cov: 32)
  • Exomes 𝑓: 0.011 (137 hom.)
• Consequence: ALPK3 NM_020778.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0790
• Publications: 10 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 (MetaRNN=0.0026003122).
• BP6: Variant 15-84858366-C-T is Benign according to our data. Variant chr15-84858366-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 383786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0528 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPK3	NM_020778.5	c.3628C>T	p.Arg1210Trp	missense_variant	Exon 6 of 14	ENST00000258888.6	NP_065829.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPK3	ENST00000258888.6	c.3628C>T	p.Arg1210Trp	missense_variant	Exon 6 of 14	1	NM_020778.5	ENSP00000258888.6

Frequencies

GnomAD3 genomes AF: 0.0222 AC: 3376 AN: 152072 Hom.: 91 Cov.: 32

Gnomad AFR AF: 0.0546

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.0102

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0110

Gnomad OTH AF: 0.0259

GnomAD2 exomes AF: 0.0117 AC: 1838 AN: 157146 AF XY: 0.0107

Gnomad AFR exome AF: 0.0550

Gnomad AMR exome AF: 0.0107

Gnomad ASJ exome AF: 0.0106

Gnomad EAS exome AF: 0.00980

Gnomad FIN exome AF: 0.000857

Gnomad NFE exome AF: 0.0118

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.0115 AC: 16097 AN: 1401888 Hom.: 137 Cov.: 36 AF XY: 0.0110 AC XY: 7602 AN XY: 692226

African (AFR) AF: 0.0543 AC: 1733 AN: 31922

American (AMR) AF: 0.0116 AC: 418 AN: 36056

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 282 AN: 25204

East Asian (EAS) AF: 0.0130 AC: 471 AN: 36168

South Asian (SAS) AF: 0.00336 AC: 268 AN: 79804

European-Finnish (FIN) AF: 0.000705 AC: 33 AN: 46824

Middle Eastern (MID) AF: 0.0109 AC: 62 AN: 5670

European-Non Finnish (NFE) AF: 0.0111 AC: 12051 AN: 1082046

Other (OTH) AF: 0.0134 AC: 779 AN: 58194

GnomAD4 genome AF: 0.0223 AC: 3387 AN: 152190 Hom.: 92 Cov.: 32 AF XY: 0.0209 AC XY: 1555 AN XY: 74418

African (AFR) AF: 0.0547 AC: 2272 AN: 41526

American (AMR) AF: 0.0123 AC: 189 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3472

East Asian (EAS) AF: 0.0101 AC: 52 AN: 5164

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4820

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10618

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0110 AC: 749 AN: 67972

Other (OTH) AF: 0.0256 AC: 54 AN: 2110

Alfa AF: 0.0138 Hom.: 65

Bravo AF: 0.0253

TwinsUK AF: 0.0108 AC: 40

ALSPAC AF: 0.0106 AC: 41

ESP6500AA AF: 0.0480 AC: 205

ESP6500EA AF: 0.0113 AC: 95

ExAC AF: 0.00753 AC: 855

Asia WGS AF: 0.0130 AC: 44 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Oct 03, 2016

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. -

Jan 23, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Arg1412Trp in exon 6 of ALPK3: This variant is not expected to have clinical s ignificance because it has been identified in 7.4% (153/2070) of African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs55752937). -

Aug 19, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Cardiomyopathy, familial hypertrophic 27 Benign:1

Oct 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Dec 26, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.079
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.10
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.23
MPC		0.14
ClinPred		0.029	T
GERP RS		0.23
Varity_R		0.22
gMVP		0.24
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs55752937; hg19: chr15-85401597; COSMIC: COSV104579861;