chr15-84858449-C-T

Variant names:

• chr15-84858449-C-T
• rs35931910
• NM_020778.5:c.3711C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020778.5(ALPK3):​c.3711C>T​(p.Asp1237Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0648 in 1,566,998 control chromosomes in the GnomAD database, including 3,411 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (355 hom., cov: 32)
  • Exomes 𝑓: 0.065 (3056 hom.)
• Consequence: ALPK3 NM_020778.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.852
• Publications: 5 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, 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 15-84858449-C-T is Benign according to our data. Variant chr15-84858449-C-T is described in ClinVar as Benign. ClinVar VariationId is 384683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.852 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0716 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALPK3	NM_020778.5	MANE Select	c.3711C>T	p.Asp1237Asp	synonymous	Exon 6 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.3711C>T	p.Asp1237Asp	synonymous	Exon 6 of 14	ENSP00000258888.6	Q96L96
	ALPK3	ENST00000934403.1		c.3672C>T	p.Asp1224Asp	synonymous	Exon 5 of 13	ENSP00000604462.1

Frequencies

GnomAD3 genomes AF: 0.0670 AC: 10184 AN: 151918 Hom.: 355 Cov.: 32

Gnomad AFR AF: 0.0708

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.0614

Gnomad ASJ AF: 0.0383

Gnomad EAS AF: 0.0779

Gnomad SAS AF: 0.0262

Gnomad FIN AF: 0.0619

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0697

Gnomad OTH AF: 0.0607

GnomAD2 exomes AF: 0.0606 AC: 10749 AN: 177506 AF XY: 0.0584

Gnomad AFR exome AF: 0.0740

Gnomad AMR exome AF: 0.0576

Gnomad ASJ exome AF: 0.0388

Gnomad EAS exome AF: 0.0804

Gnomad FIN exome AF: 0.0618

Gnomad NFE exome AF: 0.0701

Gnomad OTH exome AF: 0.0605

GnomAD4 exome AF: 0.0646 AC: 91404 AN: 1414962 Hom.: 3056 Cov.: 36 AF XY: 0.0635 AC XY: 44422 AN XY: 699956

African (AFR) AF: 0.0694 AC: 2286 AN: 32954

American (AMR) AF: 0.0584 AC: 2178 AN: 37308

Ashkenazi Jewish (ASJ) AF: 0.0366 AC: 926 AN: 25314

East Asian (EAS) AF: 0.0820 AC: 3121 AN: 38084

South Asian (SAS) AF: 0.0237 AC: 1922 AN: 80994

European-Finnish (FIN) AF: 0.0641 AC: 2800 AN: 43694

Middle Eastern (MID) AF: 0.0450 AC: 254 AN: 5646

European-Non Finnish (NFE) AF: 0.0677 AC: 73884 AN: 1092034

Other (OTH) AF: 0.0684 AC: 4033 AN: 58934

GnomAD4 genome AF: 0.0670 AC: 10189 AN: 152036 Hom.: 355 Cov.: 32 AF XY: 0.0642 AC XY: 4772 AN XY: 74310

African (AFR) AF: 0.0708 AC: 2937 AN: 41484

American (AMR) AF: 0.0613 AC: 938 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0383 AC: 133 AN: 3472

East Asian (EAS) AF: 0.0779 AC: 400 AN: 5134

South Asian (SAS) AF: 0.0262 AC: 126 AN: 4810

European-Finnish (FIN) AF: 0.0619 AC: 655 AN: 10588

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0697 AC: 4736 AN: 67934

Other (OTH) AF: 0.0596 AC: 126 AN: 2114

Alfa AF: 0.0661 Hom.: 144

Bravo AF: 0.0687

Asia WGS AF: 0.0500 AC: 173 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	not provided (2)
-	-	1	ALPK3-related disorder (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.0
DANN	Benign	0.33
PhyloP100		0.85
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: rs35931910; hg19: chr15-85401680; COSMIC: COSV51930508;