dbSNP rs1554219865: PLN:p.Leu51_Leu52insIleCysIleIleValMetLeu (chr6-118559048-T-TTGCTGATCTGTATCATCGTGA) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM4

The NM_002667.5(PLN):c.132_152dupGATCTGTATCATCGTGATGCT(p.Leu51_Leu52insIleCysIleIleValMetLeu) variant causes a disruptive inframe insertion change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

PLN
NM_002667.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.64

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a chain Phospholamban (size 51) in uniprot entity PPLA_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_002667.5

PM4

Nonframeshift variant in NON repetitive region in NM_002667.5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002667.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLN	NM_002667.5	MANE Select	c.132_152dupGATCTGTATCATCGTGATGCT	p.Leu51_Leu52insIleCysIleIleValMetLeu	disruptive_inframe_insertion	Exon 2 of 2	NP_002658.1
CEP85L	NM_001042475.3	MANE Select	c.1020+6460_1020+6480dupTCACGATGATACAGATCAGCA		intron	N/A	NP_001035940.1
CEP85L	NM_001178035.2		c.1029+6460_1029+6480dupTCACGATGATACAGATCAGCA		intron	N/A	NP_001171506.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLN	ENST00000357525.6	TSL:1 MANE Select	c.132_152dupGATCTGTATCATCGTGATGCT	p.Leu51_Leu52insIleCysIleIleValMetLeu	disruptive_inframe_insertion	Exon 2 of 2	ENSP00000350132.5
CEP85L	ENST00000368491.8	TSL:1 MANE Select	c.1020+6460_1020+6480dupTCACGATGATACAGATCAGCA		intron	N/A	ENSP00000357477.3
CEP85L	ENST00000434604.5	TSL:1	c.1029+6460_1029+6480dupTCACGATGATACAGATCAGCA		intron	N/A	ENSP00000392131.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Dilated cardiomyopathy 1P (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

6.6

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over