rs151309999

Variant names:

• chr16-28900625-G-A
• rs151309999
• NM_004320.6:c.1809G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-28900625-G-A
• chr16-28900625-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004320.6(ATP2A1):​c.1809G>A​(p.Pro603Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,593,278 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (8 hom., cov: 31)
  • Exomes 𝑓: 0.011 (111 hom.)
• Consequence: ATP2A1 NM_004320.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.936
• Publications: 1 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: Ambry Genetics, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 16-28900625-G-A is Benign according to our data. Variant chr16-28900625-G-A is described in ClinVar as Benign. ClinVar VariationId is 318779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.936 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00763 (1162/152250) while in subpopulation NFE AF = 0.011 (747/68006). AF 95% confidence interval is 0.0103. There are 8 homozygotes in GnomAd4. There are 594 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2A1	NM_004320.6	MANE Select	c.1809G>A	p.Pro603Pro	synonymous	Exon 15 of 23	NP_004311.1	O14983-2
	ATP2A1	NM_173201.5		c.1809G>A	p.Pro603Pro	synonymous	Exon 15 of 22	NP_775293.1	O14983-1
	ATP2A1	NM_001286075.2		c.1434G>A	p.Pro478Pro	synonymous	Exon 13 of 21	NP_001273004.1	O14983-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2A1	ENST00000395503.9	TSL:1 MANE Select	c.1809G>A	p.Pro603Pro	synonymous	Exon 15 of 23	ENSP00000378879.5	O14983-2
	ATP2A1	ENST00000971328.1		c.1842G>A	p.Pro614Pro	synonymous	Exon 15 of 23	ENSP00000641387.1
	ATP2A1	ENST00000357084.7	TSL:2	c.1809G>A	p.Pro603Pro	synonymous	Exon 15 of 22	ENSP00000349595.3	O14983-1

Frequencies

GnomAD3 genomes AF: 0.00764 AC: 1163 AN: 152132 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0268

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0110

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.00880 AC: 2082 AN: 236642 AF XY: 0.00887

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.0258

Gnomad NFE exome AF: 0.0129

Gnomad OTH exome AF: 0.00843

GnomAD4 exome AF: 0.0105 AC: 15159 AN: 1441028 Hom.: 111 Cov.: 32 AF XY: 0.0102 AC XY: 7308 AN XY: 713564

African (AFR) AF: 0.00144 AC: 48 AN: 33262

American (AMR) AF: 0.00202 AC: 89 AN: 44022

Ashkenazi Jewish (ASJ) AF: 0.00203 AC: 50 AN: 24638

East Asian (EAS) AF: 0.0000507 AC: 2 AN: 39412

South Asian (SAS) AF: 0.00142 AC: 118 AN: 82808

European-Finnish (FIN) AF: 0.0262 AC: 1378 AN: 52504

Middle Eastern (MID) AF: 0.00317 AC: 18 AN: 5678

European-Non Finnish (NFE) AF: 0.0118 AC: 12985 AN: 1099188

Other (OTH) AF: 0.00791 AC: 471 AN: 59516

GnomAD4 genome AF: 0.00763 AC: 1162 AN: 152250 Hom.: 8 Cov.: 31 AF XY: 0.00798 AC XY: 594 AN XY: 74440

African (AFR) AF: 0.00147 AC: 61 AN: 41548

American (AMR) AF: 0.00320 AC: 49 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.0268 AC: 284 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0110 AC: 747 AN: 68006

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00840 Hom.: 3

Bravo AF: 0.00579

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Brody myopathy (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	3.4
DANN	Benign	0.91
PhyloP100		-0.94
Mutation Taster		=96/4	polymorphism

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: rs151309999; hg19: chr16-28911946;