chr16-28878787-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_004320.6(ATP2A1):ā€‹c.116A>Gā€‹(p.Asn39Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

ATP2A1
NM_004320.6 missense, splice_region

Scores

10
7
2
Splicing: ADA: 0.03940
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.72
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-AS1 (HGNC:51370): (ATP2A1 antisense RNA 1)

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.989

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ATP2A1NM_004320.6 linkuse as main transcriptc.116A>G p.Asn39Ser missense_variant, splice_region_variant 1/23 ENST00000395503.9
ATP2A1NM_173201.5 linkuse as main transcriptc.116A>G p.Asn39Ser missense_variant, splice_region_variant 1/22

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ATP2A1ENST00000395503.9 linkuse as main transcriptc.116A>G p.Asn39Ser missense_variant, splice_region_variant 1/231 NM_004320.6 P4O14983-2
ATP2A1-AS1ENST00000691192.2 linkuse as main transcriptn.1150T>C non_coding_transcript_exon_variant 1/1
ATP2A1ENST00000357084.7 linkuse as main transcriptc.116A>G p.Asn39Ser missense_variant, splice_region_variant 1/222 A1O14983-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461638
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727136
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Brody myopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeNov 25, 2021In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with ATP2A1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 39 of the ATP2A1 protein (p.Asn39Ser). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.77
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.14
CADD
Pathogenic
30
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.79
D;.
Eigen
Pathogenic
0.98
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Pathogenic
0.88
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
0.92
D
MutationAssessor
Pathogenic
4.6
H;H
MutationTaster
Benign
1.0
D;D
PrimateAI
Benign
0.46
T
PROVEAN
Uncertain
-3.9
D;D
REVEL
Pathogenic
0.93
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.0040
D;D
Polyphen
1.0
D;D
Vest4
0.79
MutPred
0.92
Gain of phosphorylation at N39 (P = 0.0477);Gain of phosphorylation at N39 (P = 0.0477);
MVP
0.98
MPC
0.71
ClinPred
1.0
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.60
gMVP
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.039
dbscSNV1_RF
Benign
0.33
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-28890108; API