rs200246286

Positions:

• chr16-28901855-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_004320.6(ATP2A1):​c.2101-8T>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0001 in 1,612,980 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. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: ATP2A1 NM_004320.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001577
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0990

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 16-28901855-T-G is Benign according to our data. Variant chr16-28901855-T-G is described in ClinVar as [Benign]. Clinvar id is 532735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000571 (87/152330) while in subpopulation AFR AF= 0.00192 (80/41580). AF 95% confidence interval is 0.00158. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP2A1	NM_004320.6	c.2101-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000395503.9	NP_004311.1
ATP2A1	NM_001286075.2	c.1726-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001273004.1
ATP2A1	NM_173201.5	c.2101-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_775293.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP2A1	ENST00000395503.9	c.2101-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004320.6	ENSP00000378879	P4
ATP2A1	ENST00000357084.7	c.2101-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2		ENSP00000349595	A1
ATP2A1	ENST00000536376.5	c.1726-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2		ENSP00000443101

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000173 AC: 43 AN: 248930 Hom.: 0 AF XY: 0.0000817 AC XY: 11 AN XY: 134634

Gnomad AFR exome AF: 0.00224

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000513 AC: 75 AN: 1460650 Hom.: 0 Cov.: 32 AF XY: 0.0000440 AC XY: 32 AN XY: 726630

Gnomad4 AFR exome AF: 0.00179

Gnomad4 AMR exome AF: 0.0000898

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000571 AC: 87 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.000564 AC XY: 42 AN XY: 74492

Gnomad4 AFR AF: 0.00192

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000407 Hom.: 0

Bravo AF: 0.000574

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brody myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 28, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.86
DANN	Benign	0.51

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.016
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200246286; hg19: chr16-28913176;