rs143777158

Positions:

• chr16-28887633-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004320.6(ATP2A1):​c.839A>G​(p.Asn280Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000818 in 1,614,074 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (12 hom.)
• Consequence: ATP2A1 NM_004320.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.24

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013020366).
• BP6: Variant 16-28887633-A-G is Benign according to our data. Variant chr16-28887633-A-G is described in ClinVar as [Benign]. Clinvar id is 387826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00381 (580/152196) while in subpopulation AFR AF= 0.013 (541/41534). AF 95% confidence interval is 0.0121. There are 4 homozygotes in gnomad4. There are 275 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP2A1	NM_004320.6	c.839A>G	p.Asn280Ser	missense_variant	8/23	ENST00000395503.9	NP_004311.1
ATP2A1	NM_173201.5	c.839A>G	p.Asn280Ser	missense_variant	8/22		NP_775293.1
ATP2A1	NM_001286075.2	c.464A>G	p.Asn155Ser	missense_variant	6/21		NP_001273004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP2A1	ENST00000395503.9	c.839A>G	p.Asn280Ser	missense_variant	8/23	1	NM_004320.6	ENSP00000378879.5
ATP2A1	ENST00000357084.7	c.839A>G	p.Asn280Ser	missense_variant	8/22	2		ENSP00000349595.3
ATP2A1	ENST00000536376.5	c.464A>G	p.Asn155Ser	missense_variant	6/21	2		ENSP00000443101.1
ATP2A1	ENST00000564732.1	n.-32A>G		upstream_gene_variant		5		ENSP00000457357.1

Frequencies

GnomAD3 genomes AF: 0.00379 AC: 577 AN: 152078 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.000951 AC: 239 AN: 251278 Hom.: 0 AF XY: 0.000692 AC XY: 94 AN XY: 135816

Gnomad AFR exome AF: 0.0118

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000507 AC: 741 AN: 1461878 Hom.: 12 Cov.: 35 AF XY: 0.000470 AC XY: 342 AN XY: 727242

Gnomad4 AFR exome AF: 0.0152

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.000957

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000459

Gnomad4 OTH exome AF: 0.00156

GnomAD4 genome AF: 0.00381 AC: 580 AN: 152196 Hom.: 4 Cov.: 32 AF XY: 0.00370 AC XY: 275 AN XY: 74416

Gnomad4 AFR AF: 0.0130

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000764 Hom.: 2

Bravo AF: 0.00435

ESP6500AA AF: 0.0100 AC: 44

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00119 AC: 145

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jan 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Uncertain	0.70	D;.;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D;D;D
MetaRNN	Benign	0.013	T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	-0.41	N;N;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Benign	0.28
Sift	Benign	0.25	T;T;T
Sift4G	Benign	0.75	T;T;T
Polyphen		0.0010	B;B;.
Vest4		0.18
MVP		0.96
MPC		1.1
ClinPred		0.018	T
GERP RS		4.3
Varity_R		0.18
gMVP		0.67

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: rs143777158; hg19: chr16-28898954;