rs113803159

Positions:

• chr16-28887457-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_004320.6(ATP2A1):​c.663C>G​(p.Gly221=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00572 in 1,614,078 control chromosomes in the GnomAD database, including 33 homozygotes. 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 0.0045 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0059 (32 hom.)
• Consequence: ATP2A1 NM_004320.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.0840

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 16-28887457-C-G is Benign according to our data. Variant chr16-28887457-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 96544.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=3, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-0.084 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0045 (685/152228) while in subpopulation NFE AF= 0.0075 (510/67994). AF 95% confidence interval is 0.00696. There are 1 homozygotes in gnomad4. There are 324 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2A1	NM_004320.6	c.663C>G	p.Gly221=	synonymous_variant	8/23	ENST00000395503.9
ATP2A1	NM_173201.5	c.663C>G	p.Gly221=	synonymous_variant	8/22
ATP2A1	NM_001286075.2	c.288C>G	p.Gly96=	synonymous_variant	6/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2A1	ENST00000395503.9	c.663C>G	p.Gly221=	synonymous_variant	8/23	1	NM_004320.6	P4
ATP2A1	ENST00000357084.7	c.663C>G	p.Gly221=	synonymous_variant	8/22	2		A1
ATP2A1	ENST00000536376.5	c.288C>G	p.Gly96=	synonymous_variant	6/21	2

Frequencies

GnomAD3 genomes AF: 0.00451 AC: 686 AN: 152110 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00283

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00750

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00459 AC: 1150 AN: 250754 Hom.: 2 AF XY: 0.00468 AC XY: 634 AN XY: 135614

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00552

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00296

Gnomad NFE exome AF: 0.00736

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00585 AC: 8555 AN: 1461850 Hom.: 32 Cov.: 32 AF XY: 0.00577 AC XY: 4198 AN XY: 727228

Gnomad4 AFR exome AF: 0.000956

Gnomad4 AMR exome AF: 0.00503

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000452

Gnomad4 FIN exome AF: 0.00395

Gnomad4 NFE exome AF: 0.00700

Gnomad4 OTH exome AF: 0.00407

GnomAD4 genome AF: 0.00450 AC: 685 AN: 152228 Hom.: 1 Cov.: 31 AF XY: 0.00435 AC XY: 324 AN XY: 74432

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.00504

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00283

Gnomad4 NFE AF: 0.00750

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00591 Hom.: 2

Bravo AF: 0.00450

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00703

EpiControl AF: 0.00776

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 26, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	ATP2A1: BP4, BP7 -

Brody myopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Oct 29, 2019

- -

ATP2A1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 29, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	4.9
DANN	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs113803159; hg19: chr16-28898778;