rs757455246

Variant names:

• chr16-28900577-C-A
• rs757455246
• NM_004320.6:c.1765-4C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-28900577-C-A
• chr16-28900577-C-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004320.6(ATP2A1):​c.1765-4C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000711 in 1,406,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: ATP2A1 NM_004320.6 splice_region, intron
• Scores: Splicing: ADA: 0.00009802
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.34
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP2A1	NM_004320.6	c.1765-4C>A		splice_region_variant, intron_variant	Intron 14 of 22	ENST00000395503.9	NP_004311.1
ATP2A1	NM_173201.5	c.1765-4C>A		splice_region_variant, intron_variant	Intron 14 of 21		NP_775293.1
ATP2A1	NM_001286075.2	c.1390-4C>A		splice_region_variant, intron_variant	Intron 12 of 20		NP_001273004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP2A1	ENST00000395503.9	c.1765-4C>A		splice_region_variant, intron_variant	Intron 14 of 22	1	NM_004320.6	ENSP00000378879.5
ATP2A1	ENST00000357084.7	c.1765-4C>A		splice_region_variant, intron_variant	Intron 14 of 21	2		ENSP00000349595.3
ATP2A1	ENST00000536376.5	c.1390-4C>A		splice_region_variant, intron_variant	Intron 12 of 20	2		ENSP00000443101.1
ATP2A1	ENST00000564732.1	n.*408-4C>A		splice_region_variant, intron_variant	Intron 6 of 6	5		ENSP00000457357.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.11e-7 AC: 1 AN: 1406702 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 691858

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

African (AFR) AF: 0.00 AC: 0 AN: 32680

American (AMR) AF: 0.00 AC: 0 AN: 41642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22494

East Asian (EAS) AF: 0.00 AC: 0 AN: 39176

South Asian (SAS) AF: 0.00 AC: 0 AN: 76920

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5508

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1081780

Other (OTH) AF: 0.0000172 AC: 1 AN: 58146

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	2.0
DANN	Benign	0.80
PhyloP100		-1.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000098
dbscSNV1_RF	Benign	0.0
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: rs757455246; hg19: chr16-28911898;