rs151309999

Positions:

• chr16-28900625-G-A
• chr16-28900625-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004320.6(ATP2A1):​c.1809G>A​(p.Pro603=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,593,278 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (8 hom., cov: 31)
  • Exomes 𝑓: 0.011 (111 hom.)
• Consequence: ATP2A1 NM_004320.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.936

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 16-28900625-G-A is Benign according to our data. Variant chr16-28900625-G-A is described in ClinVar as [Benign]. Clinvar id is 318779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.936 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00763 (1162/152250) while in subpopulation NFE AF= 0.011 (747/68006). AF 95% confidence interval is 0.0103. There are 8 homozygotes in gnomad4. There are 594 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP2A1	NM_004320.6	c.1809G>A	p.Pro603=	synonymous_variant	15/23	ENST00000395503.9	NP_004311.1
ATP2A1	NM_173201.5	c.1809G>A	p.Pro603=	synonymous_variant	15/22		NP_775293.1
ATP2A1	NM_001286075.2	c.1434G>A	p.Pro478=	synonymous_variant	13/21		NP_001273004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP2A1	ENST00000395503.9	c.1809G>A	p.Pro603=	synonymous_variant	15/23	1	NM_004320.6	ENSP00000378879	P4
ATP2A1	ENST00000357084.7	c.1809G>A	p.Pro603=	synonymous_variant	15/22	2		ENSP00000349595	A1
ATP2A1	ENST00000536376.5	c.1434G>A	p.Pro478=	synonymous_variant	13/21	2		ENSP00000443101
ATP2A1	ENST00000564732.1			downstream_gene_variant		5		ENSP00000457357

Frequencies

GnomAD3 genomes AF: 0.00764 AC: 1163 AN: 152132 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0268

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0110

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00880 AC: 2082 AN: 236642 Hom.: 24 AF XY: 0.00887 AC XY: 1128 AN XY: 127172

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00129

Gnomad FIN exome AF: 0.0258

Gnomad NFE exome AF: 0.0129

Gnomad OTH exome AF: 0.00843

GnomAD4 exome AF: 0.0105 AC: 15159 AN: 1441028 Hom.: 111 Cov.: 32 AF XY: 0.0102 AC XY: 7308 AN XY: 713564

Gnomad4 AFR exome AF: 0.00144

Gnomad4 AMR exome AF: 0.00202

Gnomad4 ASJ exome AF: 0.00203

Gnomad4 EAS exome AF: 0.0000507

Gnomad4 SAS exome AF: 0.00142

Gnomad4 FIN exome AF: 0.0262

Gnomad4 NFE exome AF: 0.0118

Gnomad4 OTH exome AF: 0.00791

GnomAD4 genome AF: 0.00763 AC: 1162 AN: 152250 Hom.: 8 Cov.: 31 AF XY: 0.00798 AC XY: 594 AN XY: 74440

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0268

Gnomad4 NFE AF: 0.0110

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00840 Hom.: 3

Bravo AF: 0.00579

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brody myopathy Benign:2

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	ATP2A1: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 20, 2016

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	3.4
DANN	Benign	0.91

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: rs151309999; hg19: chr16-28911946;