NM_004320.6:c.1288-59G>C

Variant names:

• chr16-28894763-G-C
• rs9931989
• NM_004320.6:c.1288-59G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004320.6(ATP2A1):​c.1288-59G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.665 in 1,607,682 control chromosomes in the GnomAD database, including 359,567 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (36099 hom., cov: 29)
  • Exomes 𝑓: 0.66 (323468 hom.)
• Consequence: ATP2A1 NM_004320.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0280
• Publications: 26 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 (BayesDel_noAF=-0.8).
• BP6: Variant 16-28894763-G-C is Benign according to our data. Variant chr16-28894763-G-C is described in ClinVar as Benign. ClinVar VariationId is 678082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.859 is higher than 0.05.

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.1288-59G>C		intron	N/A	NP_004311.1	O14983-2
	ATP2A1	NM_173201.5		c.1288-59G>C		intron	N/A	NP_775293.1	O14983-1
	ATP2A1	NM_001286075.2		c.913-59G>C		intron	N/A	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.1288-59G>C		intron	N/A	ENSP00000378879.5	O14983-2
	ATP2A1	ENST00000971328.1		c.1288-59G>C		intron	N/A	ENSP00000641387.1
	ATP2A1	ENST00000357084.7	TSL:2	c.1288-59G>C		intron	N/A	ENSP00000349595.3	O14983-1

Frequencies

GnomAD3 genomes AF: 0.685 AC: 103899 AN: 151668 Hom.: 36105 Cov.: 29

Gnomad AFR AF: 0.743

Gnomad AMI AF: 0.799

Gnomad AMR AF: 0.612

Gnomad ASJ AF: 0.764

Gnomad EAS AF: 0.881

Gnomad SAS AF: 0.806

Gnomad FIN AF: 0.596

Gnomad MID AF: 0.794

Gnomad NFE AF: 0.650

Gnomad OTH AF: 0.717

GnomAD4 exome AF: 0.663 AC: 965323 AN: 1455896 Hom.: 323468 Cov.: 43 AF XY: 0.667 AC XY: 483499 AN XY: 724402

African (AFR) AF: 0.748 AC: 25034 AN: 33454

American (AMR) AF: 0.523 AC: 23379 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.764 AC: 19961 AN: 26124

East Asian (EAS) AF: 0.873 AC: 34651 AN: 39688

South Asian (SAS) AF: 0.798 AC: 68754 AN: 86138

European-Finnish (FIN) AF: 0.601 AC: 29203 AN: 48608

Middle Eastern (MID) AF: 0.816 AC: 4706 AN: 5768

European-Non Finnish (NFE) AF: 0.646 AC: 718110 AN: 1111128

Other (OTH) AF: 0.688 AC: 41525 AN: 60322

GnomAD4 genome AF: 0.685 AC: 103925 AN: 151786 Hom.: 36099 Cov.: 29 AF XY: 0.685 AC XY: 50785 AN XY: 74172

African (AFR) AF: 0.742 AC: 30731 AN: 41416

American (AMR) AF: 0.611 AC: 9313 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.764 AC: 2649 AN: 3466

East Asian (EAS) AF: 0.881 AC: 4502 AN: 5112

South Asian (SAS) AF: 0.806 AC: 3867 AN: 4800

European-Finnish (FIN) AF: 0.596 AC: 6293 AN: 10566

Middle Eastern (MID) AF: 0.803 AC: 236 AN: 294

European-Non Finnish (NFE) AF: 0.650 AC: 44104 AN: 67876

Other (OTH) AF: 0.714 AC: 1503 AN: 2104

Alfa AF: 0.656 Hom.: 4135

Bravo AF: 0.686

Asia WGS AF: 0.746 AC: 2597 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	17
DANN	Benign	0.65
PhyloP100		-0.028
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs9931989; hg19: chr16-28906084; COSMIC: COSV63920778; COSMIC: COSV63920778;