rs186012808

Positions:

• chr16-28902591-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004320.6(ATP2A1):​c.2536G>A​(p.Ala846Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000413 in 1,614,072 control chromosomes in the GnomAD database, including 3 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: 31)
  • Exomes 𝑓: 0.00040 (3 hom.)
• Consequence: ATP2A1 NM_004320.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 4.79

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0117560625).
• BP6: Variant 16-28902591-G-A is Benign according to our data. Variant chr16-28902591-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 431853.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000404 (590/1461846) while in subpopulation AFR AF= 0.00108 (36/33480). AF 95% confidence interval is 0.000798. There are 3 homozygotes in gnomad4_exome. There are 314 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP2A1	NM_004320.6	c.2536G>A	p.Ala846Thr	missense_variant	18/23	ENST00000395503.9	NP_004311.1
ATP2A1	NM_173201.5	c.2536G>A	p.Ala846Thr	missense_variant	18/22		NP_775293.1
ATP2A1	NM_001286075.2	c.2161G>A	p.Ala721Thr	missense_variant	16/21		NP_001273004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP2A1	ENST00000395503.9	c.2536G>A	p.Ala846Thr	missense_variant	18/23	1	NM_004320.6	ENSP00000378879.5
ATP2A1	ENST00000357084.7	c.2536G>A	p.Ala846Thr	missense_variant	18/22	2		ENSP00000349595.3
ATP2A1	ENST00000536376.5	c.2161G>A	p.Ala721Thr	missense_variant	16/21	2		ENSP00000443101.1

Frequencies

GnomAD3 genomes AF: 0.000500 AC: 76 AN: 152108 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000729 AC: 183 AN: 251164 Hom.: 2 AF XY: 0.000685 AC XY: 93 AN XY: 135786

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.0155

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000404 AC: 590 AN: 1461846 Hom.: 3 Cov.: 34 AF XY: 0.000432 AC XY: 314 AN XY: 727232

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.0158

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000612

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152226 Hom.: 0 Cov.: 31 AF XY: 0.000470 AC XY: 35 AN XY: 74436

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00121 Hom.: 1

Bravo AF: 0.000570

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000486 AC: 59

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000237

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 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:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 04, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D;.;.
Eigen	Benign	-0.0014
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.012	T;T;T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.1	M;M;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Uncertain	0.56
Sift	Benign	0.26	T;T;T
Sift4G	Benign	0.10	T;T;T
Polyphen		0.056	B;B;.
Vest4		0.48
MVP		0.92
MPC		0.87
ClinPred		0.027	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.54
gMVP		0.70

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: rs186012808; hg19: chr16-28913912; COSMIC: COSV62870326; COSMIC: COSV62870326;