16-28894226-C-T

Variant names:

• chr16-28894226-C-T
• rs41292388
• NM_004320.6:c.1167C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_173201.5(ATP2A1):​c.1167C>T​(p.Tyr389Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00324 in 1,613,960 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0033 (13 hom.)
• Consequence: ATP2A1 NM_173201.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -2.64
• Publications: 2 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 16-28894226-C-T is Benign according to our data. Variant chr16-28894226-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 384410.
• BP7: Synonymous conserved (PhyloP=-2.64 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00254 (386/152214) while in subpopulation NFE AF = 0.00368 (250/68010). AF 95% confidence interval is 0.0033. There are 2 homozygotes in GnomAd4. There are 167 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173201.5. 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.1167C>T	p.Tyr389Tyr	synonymous	Exon 10 of 23	NP_004311.1
	ATP2A1	NM_173201.5		c.1167C>T	p.Tyr389Tyr	synonymous	Exon 10 of 22	NP_775293.1
	ATP2A1	NM_001286075.2		c.792C>T	p.Tyr264Tyr	synonymous	Exon 8 of 21	NP_001273004.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2A1	ENST00000395503.9	TSL:1 MANE Select	c.1167C>T	p.Tyr389Tyr	synonymous	Exon 10 of 23	ENSP00000378879.5
	ATP2A1	ENST00000971328.1		c.1167C>T	p.Tyr389Tyr	synonymous	Exon 10 of 23	ENSP00000641387.1
	ATP2A1	ENST00000357084.7	TSL:2	c.1167C>T	p.Tyr389Tyr	synonymous	Exon 10 of 22	ENSP00000349595.3

Frequencies

GnomAD3 genomes AF: 0.00254 AC: 386 AN: 152096 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00396

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00368

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00285 AC: 716 AN: 251106 AF XY: 0.00274

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00339

Gnomad ASJ exome AF: 0.00586

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00337

Gnomad NFE exome AF: 0.00359

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00331 AC: 4844 AN: 1461746 Hom.: 13 Cov.: 32 AF XY: 0.00320 AC XY: 2324 AN XY: 727164

African (AFR) AF: 0.000538 AC: 18 AN: 33476

American (AMR) AF: 0.00371 AC: 166 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 143 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00107 AC: 92 AN: 86222

European-Finnish (FIN) AF: 0.00300 AC: 160 AN: 53416

Middle Eastern (MID) AF: 0.00573 AC: 33 AN: 5764

European-Non Finnish (NFE) AF: 0.00362 AC: 4022 AN: 1111930

Other (OTH) AF: 0.00344 AC: 208 AN: 60390

GnomAD4 genome AF: 0.00254 AC: 386 AN: 152214 Hom.: 2 Cov.: 31 AF XY: 0.00224 AC XY: 167 AN XY: 74418

African (AFR) AF: 0.000506 AC: 21 AN: 41532

American (AMR) AF: 0.00249 AC: 38 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00691 AC: 24 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00396 AC: 42 AN: 10610

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00368 AC: 250 AN: 68010

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00343 Hom.: 0

Bravo AF: 0.00257

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Brody myopathy (2)
-	-	2	not specified (2)
-	-	1	ATP2A1-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.17
DANN	Benign	0.52
PhyloP100		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs41292388; hg19: chr16-28905547; COSMIC: COSV63921465; COSMIC: COSV63921465;