16-28900816-G-C

Variant names:

• chr16-28900816-G-C
• rs141250244
• NM_004320.6:c.2000G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004320.6(ATP2A1):​c.2000G>C​(p.Arg667Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R667Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ATP2A1 NM_004320.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.56
• Publications: 0 publications found

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]

ATP2A1 Gene-Disease associations (from GenCC):

• Brody myopathy

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004320.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2A1	NM_004320.6	MANE Select	c.2000G>C	p.Arg667Pro	missense	Exon 15 of 23	NP_004311.1
	ATP2A1	NM_173201.5		c.2000G>C	p.Arg667Pro	missense	Exon 15 of 22	NP_775293.1
	ATP2A1	NM_001286075.2		c.1625G>C	p.Arg542Pro	missense	Exon 13 of 21	NP_001273004.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2A1	ENST00000395503.9	TSL:1 MANE Select	c.2000G>C	p.Arg667Pro	missense	Exon 15 of 23	ENSP00000378879.5
	ATP2A1	ENST00000357084.7	TSL:2	c.2000G>C	p.Arg667Pro	missense	Exon 15 of 22	ENSP00000349595.3
	ATP2A1	ENST00000536376.5	TSL:2	c.1625G>C	p.Arg542Pro	missense	Exon 13 of 21	ENSP00000443101.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Brody myopathy Uncertain:1

Dec 22, 2021

MGZ Medical Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.7	L
PhyloP100		6.6
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.62
Sift	Benign	0.17	T
Sift4G	Benign	0.22	T
Polyphen		0.0030	B
Vest4		0.50
MutPred		0.59		Loss of helix (P = 0.0376)
MVP		0.98
MPC		0.66
ClinPred		0.96	D
GERP RS		5.4
Varity_R		0.82
gMVP		0.94
Mutation Taster		=56/44	polymorphism

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

Other links and lift over

dbSNP: rs141250244; hg19: chr16-28912137;