rs143777158

Variant names:

• chr16-28887633-A-G
• rs143777158
• NM_004320.6:c.839A>G

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N280K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0038 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (12 hom.)
• Consequence: ATP2A1 NM_004320.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.24
• Publications: 3 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: Ambry Genetics, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2A1	NM_004320.6	MANE Select	c.839A>G	p.Asn280Ser	missense	Exon 8 of 23	NP_004311.1	O14983-2
	ATP2A1	NM_173201.5		c.839A>G	p.Asn280Ser	missense	Exon 8 of 22	NP_775293.1	O14983-1
	ATP2A1	NM_001286075.2		c.464A>G	p.Asn155Ser	missense	Exon 6 of 21	NP_001273004.1	O14983-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2A1	ENST00000395503.9	TSL:1 MANE Select	c.839A>G	p.Asn280Ser	missense	Exon 8 of 23	ENSP00000378879.5	O14983-2
	ATP2A1	ENST00000971328.1		c.839A>G	p.Asn280Ser	missense	Exon 8 of 23	ENSP00000641387.1
	ATP2A1	ENST00000357084.7	TSL:2	c.839A>G	p.Asn280Ser	missense	Exon 8 of 22	ENSP00000349595.3	O14983-1

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

GnomAD2 exomes AF: 0.000951 AC: 239 AN: 251278 AF XY: 0.000692

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 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

African (AFR) AF: 0.0152 AC: 509 AN: 33480

American (AMR) AF: 0.000447 AC: 20 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000957 AC: 25 AN: 26136

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

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86258

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

Middle Eastern (MID) AF: 0.00520 AC: 30 AN: 5768

European-Non Finnish (NFE) AF: 0.0000459 AC: 51 AN: 1112010

Other (OTH) AF: 0.00156 AC: 94 AN: 60396

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

African (AFR) AF: 0.0130 AC: 541 AN: 41534

American (AMR) AF: 0.00124 AC: 19 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67994

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00159 Hom.: 3

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Brody myopathy (2)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	-0.41	N
PhyloP100		3.2
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.28
Sift	Benign	0.25	T
Sift4G	Benign	0.75	T
Polyphen		0.0010	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
Mutation Taster		=91/9	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: rs143777158; hg19: chr16-28898954;