rs2071341

Variant names:

• chr16-28902389-G-T
• rs2071341
• NM_004320.6:c.2524+3G>T

Variant summary

Our verdict is Benign. The variant received -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 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. 2/3 splice prediction tools predict no significant impact on normal splicing. 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_region, intron
• Scores: Splicing: ADA: 0.9975
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.805
• Publications: 6 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 318787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
ATP2A1	NM_004320.6	c.2524+3G>T		splice_region_variant, intron_variant	Intron 17 of 22	ENST00000395503.9	NP_004311.1
ATP2A1	NM_173201.5	c.2524+3G>T		splice_region_variant, intron_variant	Intron 17 of 21		NP_775293.1
ATP2A1	NM_001286075.2	c.2149+3G>T		splice_region_variant, intron_variant	Intron 15 of 20		NP_001273004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP2A1	ENST00000395503.9	c.2524+3G>T		splice_region_variant, intron_variant	Intron 17 of 22	1	NM_004320.6	ENSP00000378879.5
ATP2A1	ENST00000357084.7	c.2524+3G>T		splice_region_variant, intron_variant	Intron 17 of 21	2		ENSP00000349595.3
ATP2A1	ENST00000536376.5	c.2149+3G>T		splice_region_variant, intron_variant	Intron 15 of 20	2		ENSP00000443101.1

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

GnomAD2 exomes AF: 0.0492 AC: 12313 AN: 250240 AF XY: 0.0463

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 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

African (AFR) AF: 0.0138 AC: 463 AN: 33472

American (AMR) AF: 0.127 AC: 5672 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00142 AC: 37 AN: 26122

East Asian (EAS) AF: 0.218 AC: 8642 AN: 39690

South Asian (SAS) AF: 0.0915 AC: 7891 AN: 86236

European-Finnish (FIN) AF: 0.000674 AC: 36 AN: 53410

Middle Eastern (MID) AF: 0.0119 AC: 68 AN: 5728

European-Non Finnish (NFE) AF: 0.00456 AC: 5073 AN: 1111810

Other (OTH) AF: 0.0257 AC: 1551 AN: 60368

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

African (AFR) AF: 0.0147 AC: 610 AN: 41504

American (AMR) AF: 0.0572 AC: 875 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.181 AC: 933 AN: 5150

South Asian (SAS) AF: 0.102 AC: 490 AN: 4822

European-Finnish (FIN) AF: 0.000566 AC: 6 AN: 10606

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00457 AC: 311 AN: 67998

Other (OTH) AF: 0.0213 AC: 45 AN: 2112

Alfa AF: 0.0152 Hom.: 72

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brody myopathy Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 01, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Feb 12, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	16
DANN	Benign	0.91
PhyloP100		0.81
Mutation Taster		=80/20	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2071341; hg19: chr16-28913710; COSMIC: COSV62869570; COSMIC: COSV62869570;