rs727503374
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_002667.5(PLN):āc.2T>Cā(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000684 in 1,461,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: not found (cov: 32)
Exomes š: 6.8e-7 ( 0 hom. )
Consequence
PLN
NM_002667.5 start_lost
NM_002667.5 start_lost
Scores
7
7
2
Clinical Significance
Conservation
PhyloP100: 6.64
Genes affected
PLN (HGNC:9080): (phospholamban) The protein encoded by this gene is found as a pentamer and is a major substrate for the cAMP-dependent protein kinase in cardiac muscle. The encoded protein is an inhibitor of cardiac muscle sarcoplasmic reticulum Ca(2+)-ATPase in the unphosphorylated state, but inhibition is relieved upon phosphorylation of the protein. The subsequent activation of the Ca(2+) pump leads to enhanced muscle relaxation rates, thereby contributing to the inotropic response elicited in heart by beta-agonists. The encoded protein is a key regulator of cardiac diastolic function. Mutations in this gene are a cause of inherited human dilated cardiomyopathy with refractory congestive heart failure, and also familial hypertrophic cardiomyopathy. [provided by RefSeq, Apr 2016]
CEP85L (HGNC:21638): (centrosomal protein 85 like) The protein encoded by this gene was identified as a breast cancer antigen. Nothing more is known of its function at this time. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLN | NM_002667.5 | c.2T>C | p.Met1? | start_lost | 2/2 | ENST00000357525.6 | |
CEP85L | NM_001042475.3 | c.1020+6606A>G | intron_variant | ENST00000368491.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLN | ENST00000357525.6 | c.2T>C | p.Met1? | start_lost | 2/2 | 1 | NM_002667.5 | P1 | |
CEP85L | ENST00000368491.8 | c.1020+6606A>G | intron_variant | 1 | NM_001042475.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461138Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1AN XY: 726936
GnomAD4 exome
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1
AN:
1461138
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Cov.:
29
AF XY:
AC XY:
1
AN XY:
726936
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
Bravo
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 20, 2013 | Variant classified as Uncertain Significance - Favor Pathogenic. The Met1? varia nt in PLN has not been previously reported in individuals with cardiomyopathy an d was absent from large population studies. This variant alters the start codon (ATG), which is expected to severely impact the protein (likely leading to an ab normal or absent protein) although the precise effect cannot be predicted. Varia nts in PLN are very rare and thus the spectrum of pathogenic variants is not wel l characterized for this gene. Additional studies are needed to fully assess the clinical significance of this variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Benign
DEOGEN2
Uncertain
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D;D;D
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
P
Vest4
MutPred
Gain of catalytic residue at M1 (P = 0.0238);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at