rs151112761

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 7P and 5B. PM1PM2PP2PP3_ModerateBS1_SupportingBS2

The NM_002667.5(PLN):c.41G>T(p.Arg14Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 152,282 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R14R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Consequence

PLN
NM_002667.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 8.28

Publications

2 publications found

Variant links:

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]

PLN links:

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]

CEP85L Gene-Disease associations (from GenCC):

lissencephaly 10
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
lissencephaly due to LIS1 mutation
Inheritance: AD Classification: STRONG Submitted by: Illumina

CEP85L links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_002667.5

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.62444 (below the threshold of 3.09). Trascript score misZ: -0.41852 (below the threshold of 3.09). GenCC associations: The gene is linked to hypertrophic cardiomyopathy 18, intrinsic cardiomyopathy, dilated cardiomyopathy 1P, arrhythmogenic right ventricular cardiomyopathy, familial isolated dilated cardiomyopathy.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.914

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000328 (5/152282) while in subpopulation AMR AF = 0.000262 (4/15278). AF 95% confidence interval is 0.0000888. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLN	NM_002667.5 link	c.41G>T	p.Arg14Ile	missense_variant	Exon 2 of 2	ENST00000357525.6	NP_002658.1	P26678Q5R352
CEP85L	NM_001042475.3 link	c.1020+6567C>A		intron_variant	Intron 3 of 12	ENST00000368491.8	NP_001035940.1	Q5SZL2-1Q3ZCQ5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLN	ENST00000357525.6 link	c.41G>T	p.Arg14Ile	missense_variant	Exon 2 of 2	1	NM_002667.5	ENSP00000350132.5		P26678
CEP85L	ENST00000368491.8 link	c.1020+6567C>A		intron_variant	Intron 3 of 12	1	NM_001042475.3	ENSP00000357477.3		Q5SZL2-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251110

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152282

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41568

American (AMR)

AF:

0.000262

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dilated cardiomyopathy 1P

Uncertain:1

Oct 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 14 of the PLN protein (p.Arg14Ile). This variant is present in population databases (rs151112761, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with PLN-related conditions. ClinVar contains an entry for this variant (Variation ID: 464270). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In 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. -

not provided

Uncertain:1

Dec 06, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published in association with a PLN-related disorder to our knowledge; This variant is associated with the following publications: (PMID: 35297759) -

Cardiovascular phenotype

Uncertain:1

Feb 27, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R14I variant (also known as c.41G>T), located in coding exon 1 of the PLN gene, results from a G to T substitution at nucleotide position 41. The arginine at codon 14 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

CardioboostCm

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.84

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.60

MetaRNN

Pathogenic

0.91

MetaSVM

Pathogenic

0.87

PhyloP100

8.3

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-8.0

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.83

MVP

0.99

MPC

1.4

ClinPred

1.0

GERP RS

5.7

Varity_R

0.97

gMVP

0.87

Mutation Taster

=20/80

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over