rs2071341

Positions:

• chr16-28902389-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_004320.6(ATP2A1):​c.2524+3G>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0203 in 1,613,700 control chromosomes in the GnomAD database, including 2,109 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (154 hom., cov: 32)
  • Exomes 𝑓: 0.020 (1955 hom.)
• Consequence: ATP2A1 NM_004320.6 splice_donor_region, intron
• Scores: Splicing: ADA: 0.9975
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.805

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 16-28902389-G-T is Benign according to our data. Variant chr16-28902389-G-T is described in ClinVar as [Benign]. Clinvar id is 318787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28902389-G-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2A1	NM_004320.6	c.2524+3G>T		splice_donor_region_variant, intron_variant		ENST00000395503.9
ATP2A1	NM_001286075.2	c.2149+3G>T		splice_donor_region_variant, intron_variant
ATP2A1	NM_173201.5	c.2524+3G>T		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2A1	ENST00000395503.9	c.2524+3G>T		splice_donor_region_variant, intron_variant		1	NM_004320.6	P4
ATP2A1	ENST00000357084.7	c.2524+3G>T		splice_donor_region_variant, intron_variant		2		A1
ATP2A1	ENST00000536376.5	c.2149+3G>T		splice_donor_region_variant, intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0215 AC: 3275 AN: 152046 Hom.: 155 Cov.: 32

Gnomad AFR AF: 0.0147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0572

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.181

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00457

Gnomad OTH AF: 0.0187

GnomAD3 exomes AF: 0.0492 AC: 12313 AN: 250240 Hom.: 936 AF XY: 0.0463 AC XY: 6273 AN XY: 135444

Gnomad AFR exome AF: 0.0153

Gnomad AMR exome AF: 0.140

Gnomad ASJ exome AF: 0.00130

Gnomad EAS exome AF: 0.184

Gnomad SAS exome AF: 0.102

Gnomad FIN exome AF: 0.000648

Gnomad NFE exome AF: 0.00453

Gnomad OTH exome AF: 0.0281

GnomAD4 exome AF: 0.0201 AC: 29433 AN: 1461536 Hom.: 1955 Cov.: 33 AF XY: 0.0213 AC XY: 15490 AN XY: 727026

Gnomad4 AFR exome AF: 0.0138

Gnomad4 AMR exome AF: 0.127

Gnomad4 ASJ exome AF: 0.00142

Gnomad4 EAS exome AF: 0.218

Gnomad4 SAS exome AF: 0.0915

Gnomad4 FIN exome AF: 0.000674

Gnomad4 NFE exome AF: 0.00456

Gnomad4 OTH exome AF: 0.0257

GnomAD4 genome AF: 0.0215 AC: 3278 AN: 152164 Hom.: 154 Cov.: 32 AF XY: 0.0243 AC XY: 1810 AN XY: 74372

Gnomad4 AFR AF: 0.0147

Gnomad4 AMR AF: 0.0572

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.181

Gnomad4 SAS AF: 0.102

Gnomad4 FIN AF: 0.000566

Gnomad4 NFE AF: 0.00457

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.00848 Hom.: 16

Bravo AF: 0.0270

Asia WGS AF: 0.151 AC: 524 AN: 3478

EpiCase AF: 0.00485

EpiControl AF: 0.00533

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brody myopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 12, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	16
DANN	Benign	0.91

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Benign	0.66
SpliceAI score (max)		0.030		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: rs2071341; hg19: chr16-28913710; COSMIC: COSV62869570; COSMIC: COSV62869570;