16-28900827-C-T

Position:

• chr16-28900827-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004320.6(ATP2A1):​c.2011C>T​(p.Arg671Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ATP2A1 NM_004320.6 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.20

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-28900827-C-T is Pathogenic according to our data. Variant chr16-28900827-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446880.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP2A1	NM_004320.6	c.2011C>T	p.Arg671Ter	stop_gained	15/23	ENST00000395503.9	NP_004311.1
ATP2A1	NM_173201.5	c.2011C>T	p.Arg671Ter	stop_gained	15/22		NP_775293.1
ATP2A1	NM_001286075.2	c.1636C>T	p.Arg546Ter	stop_gained	13/21		NP_001273004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP2A1	ENST00000395503.9	c.2011C>T	p.Arg671Ter	stop_gained	15/23	1	NM_004320.6	ENSP00000378879	P4
ATP2A1	ENST00000357084.7	c.2011C>T	p.Arg671Ter	stop_gained	15/22	2		ENSP00000349595	A1
ATP2A1	ENST00000536376.5	c.1636C>T	p.Arg546Ter	stop_gained	13/21	2		ENSP00000443101

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brody myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 11, 2023

This sequence change creates a premature translational stop signal (p.Arg671*) in the ATP2A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATP2A1 are known to be pathogenic (PMID: 8841193, 10914677, 23911890). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATP2A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 446880). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 24, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.0012
FATHMM_MKL	Benign	0.22	N
MutationTaster	Benign	1.0	A;A;A
Vest4		0.82
GERP RS		2.0

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: rs1555516994; hg19: chr16-28912148;