rs12596913

chr16-28898301-G-Achr16-28898301-G-Cchr16-28898301-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004320.6(ATP2A1):c.1614G>A(p.Thr538=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0095 in 1,614,238 control chromosomes in the GnomAD database, including 476 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T538T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.016 (69 hom., cov: 32)
  • Exomes 𝑓: 0.0088 (407 hom.)
• Consequence: ATP2A1 NM_004320.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -5.01

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=-0.84).
• BP6: Variant 16-28898301-G-A is Benign according to our data. Variant chr16-28898301-G-A is described in ClinVar as [Benign]. Clinvar id is 96540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.01 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2A1	NM_004320.6	c.1614G>A	p.Thr538=	synonymous_variant	14/23	ENST00000395503.9
ATP2A1	NM_173201.5	c.1614G>A	p.Thr538=	synonymous_variant	14/22
ATP2A1	NM_001286075.2	c.1239G>A	p.Thr413=	synonymous_variant	12/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2A1	ENST00000395503.9	c.1614G>A	p.Thr538=	synonymous_variant	14/23	1	NM_004320.6	P4
ATP2A1	ENST00000357084.7	c.1614G>A	p.Thr538=	synonymous_variant	14/22	2		A1
ATP2A1	ENST00000536376.5	c.1239G>A	p.Thr413=	synonymous_variant	12/21	2
ATP2A1	ENST00000564732.1	c.*257G>A		3_prime_UTR_variant, NMD_transcript_variant	6/7	5

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2460 AN: 152236 Hom.: 69 Cov.: 32

Gnomad AFR AF: 0.0223

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00936

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0168

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00569

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.0186 AC: 4673 AN: 251334 Hom.: 246 AF XY: 0.0169 AC XY: 2298 AN XY: 135898

Gnomad AFR exome AF: 0.0216

Gnomad AMR exome AF: 0.00688

Gnomad ASJ exome AF: 0.00764

Gnomad EAS exome AF: 0.151

Gnomad SAS exome AF: 0.00294

Gnomad FIN exome AF: 0.0180

Gnomad NFE exome AF: 0.00563

Gnomad OTH exome AF: 0.0174

GnomAD4 exome AF: 0.00881 AC: 12883 AN: 1461884 Hom.: 407 Cov.: 32 AF XY: 0.00861 AC XY: 6263 AN XY: 727242

Gnomad4 AFR exome AF: 0.0214

Gnomad4 AMR exome AF: 0.00675

Gnomad4 ASJ exome AF: 0.00742

Gnomad4 EAS exome AF: 0.117

Gnomad4 SAS exome AF: 0.00297

Gnomad4 FIN exome AF: 0.0182

Gnomad4 NFE exome AF: 0.00421

Gnomad4 OTH exome AF: 0.0173

GnomAD4 genome AF: 0.0161 AC: 2454 AN: 152354 Hom.: 69 Cov.: 32 AF XY: 0.0168 AC XY: 1251 AN XY: 74498

Gnomad4 AFR AF: 0.0222

Gnomad4 AMR AF: 0.00935

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.147

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.0168

Gnomad4 NFE AF: 0.00567

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00720 Hom.: 22

Bravo AF: 0.0159

Asia WGS AF: 0.0550 AC: 192 AN: 3478

EpiCase AF: 0.00583

EpiControl AF: 0.00634

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 01, 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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 15, 2013	- -

Brody myopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.15
Dann	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12596913; hg19: chr16-28909622;