rs66716803

Positions:

• chr16-28898456-GC-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_004320.6(ATP2A1):​c.1764+6del variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0184 in 1,612,294 control chromosomes in the GnomAD database, including 1,955 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (849 hom., cov: 31)
  • Exomes 𝑓: 0.014 (1106 hom.)
• Consequence: ATP2A1 NM_004320.6 splice_donor_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.108

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 -16 ACMG points.

• BP6: Variant 16-28898456-GC-G is Benign according to our data. Variant chr16-28898456-GC-G is described in ClinVar as [Likely_benign]. Clinvar id is 96541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP2A1	NM_004320.6	c.1764+6del		splice_donor_region_variant, intron_variant		ENST00000395503.9	NP_004311.1
ATP2A1	NM_001286075.2	c.1389+6del		splice_donor_region_variant, intron_variant			NP_001273004.1
ATP2A1	NM_173201.5	c.1764+6del		splice_donor_region_variant, intron_variant			NP_775293.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP2A1	ENST00000395503.9	c.1764+6del		splice_donor_region_variant, intron_variant		1	NM_004320.6	ENSP00000378879	P4
ATP2A1	ENST00000357084.7	c.1764+6del		splice_donor_region_variant, intron_variant		2		ENSP00000349595	A1
ATP2A1	ENST00000536376.5	c.1389+6del		splice_donor_region_variant, intron_variant		2		ENSP00000443101
ATP2A1	ENST00000564732.1	c.*407+6del		splice_donor_region_variant, intron_variant, NMD_transcript_variant		5		ENSP00000457357

Frequencies

GnomAD3 genomes AF: 0.0637 AC: 9692 AN: 152158 Hom.: 848 Cov.: 31

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0232

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0170

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00614

Gnomad OTH AF: 0.0425

GnomAD3 exomes AF: 0.0312 AC: 7554 AN: 242494 Hom.: 512 AF XY: 0.0258 AC XY: 3413 AN XY: 132148

Gnomad AFR exome AF: 0.193

Gnomad AMR exome AF: 0.0159

Gnomad ASJ exome AF: 0.00780

Gnomad EAS exome AF: 0.151

Gnomad SAS exome AF: 0.00297

Gnomad FIN exome AF: 0.0178

Gnomad NFE exome AF: 0.00597

Gnomad OTH exome AF: 0.0251

GnomAD4 exome AF: 0.0137 AC: 19997 AN: 1460018 Hom.: 1106 Cov.: 31 AF XY: 0.0128 AC XY: 9302 AN XY: 726260

Gnomad4 AFR exome AF: 0.195

Gnomad4 AMR exome AF: 0.0169

Gnomad4 ASJ exome AF: 0.00751

Gnomad4 EAS exome AF: 0.116

Gnomad4 SAS exome AF: 0.00309

Gnomad4 FIN exome AF: 0.0181

Gnomad4 NFE exome AF: 0.00437

Gnomad4 OTH exome AF: 0.0285

GnomAD4 genome AF: 0.0638 AC: 9711 AN: 152276 Hom.: 849 Cov.: 31 AF XY: 0.0622 AC XY: 4629 AN XY: 74464

Gnomad4 AFR AF: 0.190

Gnomad4 AMR AF: 0.0232

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.147

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0170

Gnomad4 NFE AF: 0.00613

Gnomad4 OTH AF: 0.0426

Alfa AF: 0.00761 Hom.: 8

Bravo AF: 0.0702

Asia WGS AF: 0.0680 AC: 235 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brody myopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 15, 2013

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 22, 2018

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs66716803; hg19: chr16-28909777;