rs150068594

Positions:

• chr16-28898007-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_004320.6(ATP2A1):​c.1427G>A​(p.Arg476His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000152 in 1,614,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: ATP2A1 NM_004320.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 7.62

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 -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.033347398).
• BP6: Variant 16-28898007-G-A is Benign according to our data. Variant chr16-28898007-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 464076.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00048 (73/152232) while in subpopulation AFR AF= 0.00156 (65/41536). AF 95% confidence interval is 0.00126. There are 0 homozygotes in gnomad4. There are 33 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2A1	NM_004320.6	c.1427G>A	p.Arg476His	missense_variant	13/23	ENST00000395503.9
ATP2A1	NM_173201.5	c.1427G>A	p.Arg476His	missense_variant	13/22
ATP2A1	NM_001286075.2	c.1052G>A	p.Arg351His	missense_variant	11/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2A1	ENST00000395503.9	c.1427G>A	p.Arg476His	missense_variant	13/23	1	NM_004320.6	P4
ATP2A1	ENST00000357084.7	c.1427G>A	p.Arg476His	missense_variant	13/22	2		A1
ATP2A1	ENST00000536376.5	c.1052G>A	p.Arg351His	missense_variant	11/21	2
ATP2A1	ENST00000564732.1	c.*70G>A		3_prime_UTR_variant, NMD_transcript_variant	5/7	5

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 73 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000131 AC: 33 AN: 251448 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135898

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000118 AC: 172 AN: 1461850 Hom.: 0 Cov.: 32 AF XY: 0.0000976 AC XY: 71 AN XY: 727228

Gnomad4 AFR exome AF: 0.00164

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000890

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000480 AC: 73 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33 AN XY: 74432

Gnomad4 AFR AF: 0.00156

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.000608

ESP6500AA AF: 0.000910 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000157 AC: 19

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Brody myopathy Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 16, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 19, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 476 of the ATP2A1 protein (p.Arg476His). This variant is present in population databases (rs150068594, gnomAD 0.2%). 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: 464076). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

ATP2A1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 02, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;.;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.033	T;T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.6	L;L;.
MutationTaster	Benign	0.94	D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.060	T;T;T
Sift4G	Uncertain	0.044	D;D;D
Polyphen		0.0010	B;B;.
Vest4		0.49
MVP		0.85
MPC		0.92
ClinPred		0.11	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.45

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: rs150068594; hg19: chr16-28909328; COSMIC: COSV100837247; COSMIC: COSV100837247;