Genetic Variant ALPK3:c.-83C>G (chr15-84817370-C-G) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_020778.5(ALPK3):c.-83C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000662 in 1,224,388 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

ALPK3
NM_020778.5 5_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -0.942

Publications

1 publications found

Variant links:

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, AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen
cardiomyopathy, familial hypertrophic 27
Inheritance: AR, AD, SD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ALPK3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.041144013).

BP6

Variant 15-84817370-C-G is Benign according to our data. Variant chr15-84817370-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2504925.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALPK3	NM_020778.5	MANE Select	c.-83C>G		5_prime_UTR	Exon 1 of 14	NP_065829.4	Q96L96

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALPK3	ENST00000258888.6	TSL:1 MANE Select	c.-83C>G		5_prime_UTR	Exon 1 of 14	ENSP00000258888.6	Q96L96
	ALPK3	ENST00000934403.1		c.-83C>G		5_prime_UTR	Exon 1 of 13	ENSP00000604462.1

Frequencies

GnomAD3 genomes

AF:

0.0000397

AC:

AN:

151128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000591

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000699

AC:

AN:

1073260

Hom.:

Cov.:

AF XY:

0.0000669

AC XY:

AN XY:

507924

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22314

American (AMR)

AF:

0.00

AC:

AN:

7904

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13682

East Asian (EAS)

AF:

0.00

AC:

AN:

25204

South Asian (SAS)

AF:

0.00

AC:

AN:

20380

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21202

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2852

European-Non Finnish (NFE)

AF:

0.0000774

AC:

AN:

916904

Other (OTH)

AF:

0.0000934

AC:

AN:

42818

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000397

AC:

AN:

151128

Hom.:

Cov.:

AF XY:

0.0000271

AC XY:

AN XY:

73770

show subpopulations

African (AFR)

AF:

0.0000484

AC:

AN:

41330

American (AMR)

AF:

0.00

AC:

AN:

15154

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10238

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000591

AC:

AN:

67686

Other (OTH)

AF:

0.00

AC:

AN:

2072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000378

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0055

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.29

M_CAP

Benign

0.036

MetaRNN

Benign

0.041

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.34

PhyloP100

-0.94

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.33

REVEL

Benign

0.084

Sift

Benign

0.35

Sift4G

Benign

0.40

Polyphen

0.0020

Vest4

0.11

MutPred

0.26

Gain of relative solvent accessibility (P = 0.0023)

MVP

0.28

MPC

1.0

ClinPred

0.053

GERP RS

0.15

PromoterAI

-0.19

Neutral

(source)

Varity_R

0.051

gMVP

0.094

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over