16-28900816-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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 (★).

• 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

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 Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP2A1	NM_004320.6	c.2000G>C	p.Arg667Pro	missense_variant	Exon 15 of 23	ENST00000395503.9	NP_004311.1
ATP2A1	NM_173201.5	c.2000G>C	p.Arg667Pro	missense_variant	Exon 15 of 22		NP_775293.1
ATP2A1	NM_001286075.2	c.1625G>C	p.Arg542Pro	missense_variant	Exon 13 of 21		NP_001273004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP2A1	ENST00000395503.9	c.2000G>C	p.Arg667Pro	missense_variant	Exon 15 of 23	1	NM_004320.6	ENSP00000378879.5
ATP2A1	ENST00000357084.7	c.2000G>C	p.Arg667Pro	missense_variant	Exon 15 of 22	2		ENSP00000349595.3
ATP2A1	ENST00000536376.5	c.1625G>C	p.Arg542Pro	missense_variant	Exon 13 of 21	2		ENSP00000443101.1
ATP2A1	ENST00000564732.1	n.*643G>C		downstream_gene_variant		5		ENSP00000457357.1

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

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

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

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Computational scores

Source: dbNSFP v4.3

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;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.7	L;L;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-4.5	D;D;D
REVEL	Uncertain	0.62
Sift	Benign	0.17	T;T;T
Sift4G	Benign	0.22	T;T;T
Polyphen		0.0030	B;B;.
Vest4		0.50
MutPred		0.59		Loss of helix (P = 0.0376);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

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-28912137;