16-28902318-GC-GCC

Variant names:

• chr16-28902318-G-GC
• rs751365374
• NM_004320.6:c.2464dupC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_004320.6(ATP2A1):​c.2464dupC​(p.Arg822ProfsTer39) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000242 in 1,612,038 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: ATP2A1 NM_004320.6 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 0.140
• Publications: 9 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: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 16-28902318-G-GC is Pathogenic according to our data. Variant chr16-28902318-G-GC is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 464085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2464dupC	p.Arg822ProfsTer39	frameshift	Exon 17 of 23	NP_004311.1	O14983-2
	ATP2A1	NM_173201.5		c.2464dupC	p.Arg822ProfsTer39	frameshift	Exon 17 of 22	NP_775293.1	O14983-1
	ATP2A1	NM_001286075.2		c.2089dupC	p.Arg697ProfsTer39	frameshift	Exon 15 of 21	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.2464dupC	p.Arg822ProfsTer39	frameshift	Exon 17 of 23	ENSP00000378879.5	O14983-2
	ATP2A1	ENST00000971328.1		c.2497dupC	p.Arg833ProfsTer39	frameshift	Exon 17 of 23	ENSP00000641387.1
	ATP2A1	ENST00000357084.7	TSL:2	c.2464dupC	p.Arg822ProfsTer39	frameshift	Exon 17 of 22	ENSP00000349595.3	O14983-1

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 151532 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000242

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: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000354 AC: 88 AN: 248542 AF XY: 0.000148

Gnomad AFR exome AF: 0.000633

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.000504

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000599

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000253 AC: 370 AN: 1460506 Hom.: 0 Cov.: 33 AF XY: 0.000234 AC XY: 170 AN XY: 726506

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000299 AC: 10 AN: 33464

American (AMR) AF: 0.0000447 AC: 2 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86238

European-Finnish (FIN) AF: 0.00252 AC: 133 AN: 52828

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.000184 AC: 204 AN: 1111350

Other (OTH) AF: 0.000199 AC: 12 AN: 60340

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000132 AC: 20 AN: 151532 Hom.: 0 Cov.: 32 AF XY: 0.000176 AC XY: 13 AN XY: 73954

African (AFR) AF: 0.000242 AC: 10 AN: 41254

American (AMR) AF: 0.00 AC: 0 AN: 15194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67834

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.000691 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Brody myopathy (5)
2	-	-	not provided (2)
1	-	-	ATP2A1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.14
Mutation Taster		=5/195	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs751365374; hg19: chr16-28913639; COSMIC: COSV62868738; COSMIC: COSV62868738;