chr16-28887709-T-C

Variant names:

• chr16-28887709-T-C
• rs1555515559
• NM_004320.6:c.915T>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_004320.6(ATP2A1):​c.915T>C​(p.Ala305Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A305A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP2A1 NM_004320.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.51
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP7: Synonymous conserved (PhyloP=-1.51 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP2A1	NM_004320.6	c.915T>C	p.Ala305Ala	synonymous_variant	Exon 8 of 23	ENST00000395503.9	NP_004311.1
ATP2A1	NM_173201.5	c.915T>C	p.Ala305Ala	synonymous_variant	Exon 8 of 22		NP_775293.1
ATP2A1	NM_001286075.2	c.540T>C	p.Ala180Ala	synonymous_variant	Exon 6 of 21		NP_001273004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP2A1	ENST00000395503.9	c.915T>C	p.Ala305Ala	synonymous_variant	Exon 8 of 23	1	NM_004320.6	ENSP00000378879.5
ATP2A1	ENST00000357084.7	c.915T>C	p.Ala305Ala	synonymous_variant	Exon 8 of 22	2		ENSP00000349595.3
ATP2A1	ENST00000536376.5	c.540T>C	p.Ala180Ala	synonymous_variant	Exon 6 of 21	2		ENSP00000443101.1
ATP2A1	ENST00000564732.1	n.45T>C		non_coding_transcript_exon_variant	Exon 1 of 7	5		ENSP00000457357.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	1.8
DANN	Benign	0.65
PhyloP100		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1555515559; hg19: chr16-28899030;