16-28894763-G-C

Position:

• chr16-28894763-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004320.6(ATP2A1):​c.1288-59G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.665 in 1,607,682 control chromosomes in the GnomAD database, including 359,567 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (36099 hom., cov: 29)
  • Exomes 𝑓: 0.66 (323468 hom.)
• Consequence: ATP2A1 NM_004320.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0280

Genes affected

ATP2A1 (HGNC:811): (ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 1) This gene encodes one of the SERCA Ca(2+)-ATPases, which are intracellular pumps located in the sarcoplasmic or endoplasmic reticula of muscle cells. This enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen, and is involved in muscular excitation and contraction. Mutations in this gene cause some autosomal recessive forms of Brody disease, characterized by increasing impairment of muscular relaxation during exercise. Alternative splicing results in three transcript variants encoding different isoforms. [provided by RefSeq, Oct 2013]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 16-28894763-G-C is Benign according to our data. Variant chr16-28894763-G-C is described in ClinVar as [Benign]. Clinvar id is 678082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.859 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP2A1	NM_004320.6	c.1288-59G>C		intron_variant		ENST00000395503.9	NP_004311.1
ATP2A1	NM_173201.5	c.1288-59G>C		intron_variant			NP_775293.1
ATP2A1	NM_001286075.2	c.913-59G>C		intron_variant			NP_001273004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP2A1	ENST00000395503.9	c.1288-59G>C		intron_variant		1	NM_004320.6	ENSP00000378879.5
ATP2A1	ENST00000357084.7	c.1288-59G>C		intron_variant		2		ENSP00000349595.3
ATP2A1	ENST00000536376.5	c.913-59G>C		intron_variant		2		ENSP00000443101.1
ATP2A1	ENST00000564732.1	n.315-59G>C		intron_variant		5		ENSP00000457357.1

Frequencies

GnomAD3 genomes AF: 0.685 AC: 103899 AN: 151668 Hom.: 36105 Cov.: 29

Gnomad AFR AF: 0.743

Gnomad AMI AF: 0.799

Gnomad AMR AF: 0.612

Gnomad ASJ AF: 0.764

Gnomad EAS AF: 0.881

Gnomad SAS AF: 0.806

Gnomad FIN AF: 0.596

Gnomad MID AF: 0.794

Gnomad NFE AF: 0.650

Gnomad OTH AF: 0.717

GnomAD4 exome AF: 0.663 AC: 965323 AN: 1455896 Hom.: 323468 Cov.: 43 AF XY: 0.667 AC XY: 483499 AN XY: 724402

Gnomad4 AFR exome AF: 0.748

Gnomad4 AMR exome AF: 0.523

Gnomad4 ASJ exome AF: 0.764

Gnomad4 EAS exome AF: 0.873

Gnomad4 SAS exome AF: 0.798

Gnomad4 FIN exome AF: 0.601

Gnomad4 NFE exome AF: 0.646

Gnomad4 OTH exome AF: 0.688

GnomAD4 genome AF: 0.685 AC: 103925 AN: 151786 Hom.: 36099 Cov.: 29 AF XY: 0.685 AC XY: 50785 AN XY: 74172

Gnomad4 AFR AF: 0.742

Gnomad4 AMR AF: 0.611

Gnomad4 ASJ AF: 0.764

Gnomad4 EAS AF: 0.881

Gnomad4 SAS AF: 0.806

Gnomad4 FIN AF: 0.596

Gnomad4 NFE AF: 0.650

Gnomad4 OTH AF: 0.714

Alfa AF: 0.656 Hom.: 4135

Bravo AF: 0.686

Asia WGS AF: 0.746 AC: 2597 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	17
DANN	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs9931989; hg19: chr16-28906084; COSMIC: COSV63920778; COSMIC: COSV63920778;