6-118558946-C-G

Variant names:

• chr6-118558946-C-G
• rs111033559
• NM_002667.5:c.25C>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_002667.5(PLN):​c.25C>G​(p.Arg9Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R9H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PLN NM_002667.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.55
• Publications: 0 publications found

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]

CEP85L Gene-Disease associations (from GenCC):

• lissencephaly 10

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen
• lissencephaly due to LIS1 mutation

  Inheritance: AD Classification: STRONG Submitted by: Illumina

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 30) in uniprot entity PPLA_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_002667.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-118558947-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 202037.
• 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 dilated cardiomyopathy 1P, intrinsic cardiomyopathy, familial isolated dilated cardiomyopathy, hypertrophic cardiomyopathy 18, arrhythmogenic right ventricular cardiomyopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLN	NM_002667.5	MANE Select	c.25C>G	p.Arg9Gly	missense	Exon 2 of 2	NP_002658.1	P26678
	CEP85L	NM_001042475.3	MANE Select	c.1020+6583G>C		intron	N/A	NP_001035940.1	Q5SZL2-1
	CEP85L	NM_001178035.2		c.1029+6583G>C		intron	N/A	NP_001171506.1	Q5SZL2-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLN	ENST00000357525.6	TSL:1 MANE Select	c.25C>G	p.Arg9Gly	missense	Exon 2 of 2	ENSP00000350132.5	P26678
	CEP85L	ENST00000368491.8	TSL:1 MANE Select	c.1020+6583G>C		intron	N/A	ENSP00000357477.3	Q5SZL2-1
	CEP85L	ENST00000434604.5	TSL:1	c.1029+6583G>C		intron	N/A	ENSP00000392131.1	A2A3P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461452 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 727074

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111630

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
CardioboostCm	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.70	D
PhyloP100		6.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.017	D
Polyphen		0.87	P
Vest4		0.87
MutPred		0.81		Loss of MoRF binding (P = 0.0047)
MVP		0.99
MPC		1.1
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.90
gMVP		0.78
Mutation Taster		=25/75	disease causing

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

Other links and lift over

dbSNP: rs111033559; hg19: chr6-118880109;