rs138565447

Positions:

• chr16-28898247-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_004320.6(ATP2A1):​c.1560C>T​(p.Gly520Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000934 in 1,614,106 control chromosomes in the GnomAD database, including 2 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 0.00050 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (2 hom.)
• Consequence: ATP2A1 NM_004320.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -1.59

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 16-28898247-C-T is Benign according to our data. Variant chr16-28898247-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 318776.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-1.59 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000499 (76/152224) while in subpopulation NFE AF= 0.000941 (64/68048). AF 95% confidence interval is 0.000755. There are 0 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP2A1	NM_004320.6	c.1560C>T	p.Gly520Gly	synonymous_variant	14/23	ENST00000395503.9	NP_004311.1
ATP2A1	NM_173201.5	c.1560C>T	p.Gly520Gly	synonymous_variant	14/22		NP_775293.1
ATP2A1	NM_001286075.2	c.1185C>T	p.Gly395Gly	synonymous_variant	12/21		NP_001273004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP2A1	ENST00000395503.9	c.1560C>T	p.Gly520Gly	synonymous_variant	14/23	1	NM_004320.6	ENSP00000378879.5

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 76 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000461 AC: 116 AN: 251406 Hom.: 0 AF XY: 0.000574 AC XY: 78 AN XY: 135908

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000897

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000980 AC: 1432 AN: 1461882 Hom.: 2 Cov.: 32 AF XY: 0.00101 AC XY: 732 AN XY: 727246

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.00123

Gnomad4 OTH exome AF: 0.000712

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74358

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.000941

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000610 Hom.: 0

Bravo AF: 0.000480

EpiCase AF: 0.00115

EpiControl AF: 0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Brody myopathy Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 26, 2020

- -

ATP2A1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 22, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	4.9
DANN	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs138565447; hg19: chr16-28909568;