16-28898301-G-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004320.6(ATP2A1):​c.1614G>A​(p.Thr538Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0095 in 1,614,238 control chromosomes in the GnomAD database, including 476 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T538T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.016 ( 69 hom., cov: 32)
Exomes 𝑓: 0.0088 ( 407 hom. )

Consequence

ATP2A1
NM_004320.6 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -5.01

Publications

6 publications found
Variant links:
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.84).
BP6
Variant 16-28898301-G-A is Benign according to our data. Variant chr16-28898301-G-A is described in ClinVar as [Benign]. Clinvar id is 96540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-5.01 with no splicing effect.
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATP2A1NM_004320.6 linkc.1614G>A p.Thr538Thr synonymous_variant Exon 14 of 23 ENST00000395503.9 NP_004311.1 O14983-2Q7Z675
ATP2A1NM_173201.5 linkc.1614G>A p.Thr538Thr synonymous_variant Exon 14 of 22 NP_775293.1 O14983-1Q7Z675
ATP2A1NM_001286075.2 linkc.1239G>A p.Thr413Thr synonymous_variant Exon 12 of 21 NP_001273004.1 O14983-3Q7Z675

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATP2A1ENST00000395503.9 linkc.1614G>A p.Thr538Thr synonymous_variant Exon 14 of 23 1 NM_004320.6 ENSP00000378879.5 O14983-2

Frequencies

GnomAD3 genomes
AF:
0.0162
AC:
2460
AN:
152236
Hom.:
69
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0223
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00936
Gnomad ASJ
AF:
0.00490
Gnomad EAS
AF:
0.148
Gnomad SAS
AF:
0.00248
Gnomad FIN
AF:
0.0168
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00569
Gnomad OTH
AF:
0.0134
GnomAD2 exomes
AF:
0.0186
AC:
4673
AN:
251334
AF XY:
0.0169
show subpopulations
Gnomad AFR exome
AF:
0.0216
Gnomad AMR exome
AF:
0.00688
Gnomad ASJ exome
AF:
0.00764
Gnomad EAS exome
AF:
0.151
Gnomad FIN exome
AF:
0.0180
Gnomad NFE exome
AF:
0.00563
Gnomad OTH exome
AF:
0.0174
GnomAD4 exome
AF:
0.00881
AC:
12883
AN:
1461884
Hom.:
407
Cov.:
32
AF XY:
0.00861
AC XY:
6263
AN XY:
727242
show subpopulations
African (AFR)
AF:
0.0214
AC:
717
AN:
33480
American (AMR)
AF:
0.00675
AC:
302
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00742
AC:
194
AN:
26136
East Asian (EAS)
AF:
0.117
AC:
4628
AN:
39700
South Asian (SAS)
AF:
0.00297
AC:
256
AN:
86258
European-Finnish (FIN)
AF:
0.0182
AC:
970
AN:
53410
Middle Eastern (MID)
AF:
0.0147
AC:
85
AN:
5768
European-Non Finnish (NFE)
AF:
0.00421
AC:
4685
AN:
1112012
Other (OTH)
AF:
0.0173
AC:
1046
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.487
Heterozygous variant carriers
0
881
1762
2642
3523
4404
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
242
484
726
968
1210
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0161
AC:
2454
AN:
152354
Hom.:
69
Cov.:
32
AF XY:
0.0168
AC XY:
1251
AN XY:
74498
show subpopulations
African (AFR)
AF:
0.0222
AC:
925
AN:
41588
American (AMR)
AF:
0.00935
AC:
143
AN:
15298
Ashkenazi Jewish (ASJ)
AF:
0.00490
AC:
17
AN:
3472
East Asian (EAS)
AF:
0.147
AC:
766
AN:
5194
South Asian (SAS)
AF:
0.00207
AC:
10
AN:
4832
European-Finnish (FIN)
AF:
0.0168
AC:
178
AN:
10616
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00567
AC:
386
AN:
68034
Other (OTH)
AF:
0.0137
AC:
29
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.499
Heterozygous variant carriers
0
125
251
376
502
627
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
32
64
96
128
160
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00870
Hom.:
39
Bravo
AF:
0.0159
Asia WGS
AF:
0.0550
AC:
192
AN:
3478
EpiCase
AF:
0.00583
EpiControl
AF:
0.00634

ClinVar

Significance: Benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Apr 01, 2016
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jan 15, 2013
Eurofins Ntd Llc (ga)
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Oct 16, 2023
Athena Diagnostics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Brody myopathy Benign:2
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.84
CADD
Benign
0.15
DANN
Benign
0.58
PhyloP100
-5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Mutation Taster
=100/0
polymorphism (auto)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs12596913; hg19: chr16-28909622; COSMIC: COSV107451982; COSMIC: COSV107451982; API