17-3930371-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_005173.4(ATP2A3):c.2674G>A(p.Glu892Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00415 in 1,613,738 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts 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. E892G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0030 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0043 (26 hom.)
• Consequence: ATP2A3 NM_005173.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.17

Genes affected

ATP2A3 (HGNC:813): (ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 3) 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 calcium sequestration associated with muscular excitation and contraction. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021290064).
• BP6: Variant 17-3930371-C-T is Benign according to our data. Variant chr17-3930371-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3041510.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2A3	NM_005173.4	c.2674G>A	p.Glu892Lys	missense_variant	18/21	ENST00000397041.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2A3	ENST00000397041.8	c.2674G>A	p.Glu892Lys	missense_variant	18/21	1	NM_005173.4	P1

Frequencies

GnomAD3 genomes AF: 0.00300 AC: 457 AN: 152250 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00486

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00328 AC: 818 AN: 249296 Hom.: 0 AF XY: 0.00333 AC XY: 450 AN XY: 135134

Gnomad AFR exome AF: 0.00100

Gnomad AMR exome AF: 0.00395

Gnomad ASJ exome AF: 0.00220

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000394

Gnomad FIN exome AF: 0.00177

Gnomad NFE exome AF: 0.00507

Gnomad OTH exome AF: 0.00395

GnomAD4 exome AF: 0.00427 AC: 6235 AN: 1461370 Hom.: 26 Cov.: 33 AF XY: 0.00418 AC XY: 3040 AN XY: 726944

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00379

Gnomad4 ASJ exome AF: 0.00226

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000395

Gnomad4 FIN exome AF: 0.00240

Gnomad4 NFE exome AF: 0.00503

Gnomad4 OTH exome AF: 0.00366

GnomAD4 genome AF: 0.00300 AC: 457 AN: 152368 Hom.: 4 Cov.: 31 AF XY: 0.00287 AC XY: 214 AN XY: 74508

Gnomad4 AFR AF: 0.000769

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00207

Gnomad4 NFE AF: 0.00487

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00431 Hom.: 4

Bravo AF: 0.00312

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00581 AC: 50

ExAC AF: 0.00327 AC: 396

EpiCase AF: 0.00480

EpiControl AF: 0.00505

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ATP2A3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 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	0.16
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Pathogenic	0.25
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.032
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D;.;D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.016	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.013	T
MutationAssessor	Benign	1.9	M;M;M;.;M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.3	N;N;N;.;N;N;N;.
REVEL	Uncertain	0.61
Sift	Benign	0.20	T;T;T;.;T;T;T;.
Sift4G	Benign	0.42	T;T;T;D;T;T;T;D
Polyphen		0.0060	B;B;B;.;.;B;P;.
Vest4		0.71
MVP		0.69
MPC		0.77
ClinPred		0.038	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.35
gMVP		0.93

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: rs141235119; hg19: chr17-3833665; COSMIC: COSV99989981; COSMIC: COSV99989981;