rs188578681

Positions:

• chr6-118548254-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001042475.3(CEP85L):​c.1020+17275G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000322 in 152,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CEP85L NM_001042475.3 intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:3
• Conservation: PhyloP100: 2.72

Genes affected

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]

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BS2: High AC in GnomAd4 at 49 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP85L	NM_001042475.3	c.1020+17275G>C		intron_variant		ENST00000368491.8	NP_001035940.1
PLN	NM_002667.5			upstream_gene_variant		ENST00000357525.6	NP_002658.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP85L	ENST00000368491.8	c.1020+17275G>C		intron_variant		1	NM_001042475.3	ENSP00000357477	P1
PLN	ENST00000357525.6			upstream_gene_variant		1	NM_002667.5	ENSP00000350132	P1

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 151974 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00144

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 12 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 12

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152092 Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 24 AN XY: 74370

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.00125

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.000347 Hom.: 0

Bravo AF: 0.000608

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy 18 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2007

- -

Dilated cardiomyopathy 1P Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 13, 2022

This variant occurs in a non-coding region of the PLN gene. It does not change the encoded amino acid sequence of the PLN protein. This variant is present in population databases (rs188578681, gnomAD 0.2%). 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: 220851). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

PLN-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 27, 2024

The PLN c.-236C>G variant is located in the 5' untranslated region. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.24% of alleles in individuals of Latino descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Dilated cardiomyopathy 1P;C3151265:Hypertrophic cardiomyopathy 18 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 05, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Benign	0.77

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

LitVar

Other links and lift over

dbSNP: rs188578681; hg19: chr6-118869417;