chr16-28900667-C-A

Variant names:

• chr16-28900667-C-A
• rs140547832
• NM_004320.6:c.1851C>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_004320.6(ATP2A1):​c.1851C>A​(p.Ala617Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000373 in 1,609,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. A617A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ATP2A1 NM_004320.6 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.12
• Publications: 0 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 16-28900667-C-A is Benign according to our data. Variant chr16-28900667-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3702884.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-4.12 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2A1	NM_004320.6	MANE Select	c.1851C>A	p.Ala617Ala	synonymous	Exon 15 of 23	NP_004311.1
	ATP2A1	NM_173201.5		c.1851C>A	p.Ala617Ala	synonymous	Exon 15 of 22	NP_775293.1
	ATP2A1	NM_001286075.2		c.1476C>A	p.Ala492Ala	synonymous	Exon 13 of 21	NP_001273004.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2A1	ENST00000395503.9	TSL:1 MANE Select	c.1851C>A	p.Ala617Ala	synonymous	Exon 15 of 23	ENSP00000378879.5
	ATP2A1	ENST00000357084.7	TSL:2	c.1851C>A	p.Ala617Ala	synonymous	Exon 15 of 22	ENSP00000349595.3
	ATP2A1	ENST00000536376.5	TSL:2	c.1476C>A	p.Ala492Ala	synonymous	Exon 13 of 21	ENSP00000443101.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249142 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000894

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1457810 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 724292

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26018

East Asian (EAS) AF: 0.00 AC: 0 AN: 39576

South Asian (SAS) AF: 0.00 AC: 0 AN: 86090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1108736

Other (OTH) AF: 0.0000166 AC: 1 AN: 60238

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74326

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Brody myopathy Benign:1

May 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.078
DANN	Benign	0.89
PhyloP100		-4.1

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: rs140547832; hg19: chr16-28911988;