rs77186188

Positions:

• chr6-118548260-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001042475.3(CEP85L):​c.1020+17269T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0403 in 152,116 control chromosomes in the GnomAD database, including 198 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (198 hom., cov: 32)
  • Exomes 𝑓: 0.071 (0 hom.)
• Consequence: CEP85L NM_001042475.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:4
• Conservation: PhyloP100: 1.38

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 6-118548260-A-C is Benign according to our data. Variant chr6-118548260-A-C is described in ClinVar as [Benign]. Clinvar id is 403328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0585 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP85L	NM_001042475.3	c.1020+17269T>G		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+17269T>G		intron_variant		1	NM_001042475.3	ENSP00000357477	P1
PLN	ENST00000357525.6			upstream_gene_variant		1	NM_002667.5	ENSP00000350132	P1

Frequencies

GnomAD3 genomes AF: 0.0403 AC: 6130 AN: 151984 Hom.: 199 Cov.: 32

Gnomad AFR AF: 0.00913

Gnomad AMI AF: 0.0582

Gnomad AMR AF: 0.0264

Gnomad ASJ AF: 0.0490

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0160

Gnomad FIN AF: 0.0852

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0601

Gnomad OTH AF: 0.0298

GnomAD4 exome AF: 0.0714 AC: 1 AN: 14 Hom.: 0 Cov.: 0 AF XY: 0.0833 AC XY: 1 AN XY: 12

Gnomad4 AMR exome AF: 0.00

Gnomad4 NFE exome AF: 0.0833

GnomAD4 genome AF: 0.0403 AC: 6128 AN: 152102 Hom.: 198 Cov.: 32 AF XY: 0.0398 AC XY: 2956 AN XY: 74356

Gnomad4 AFR AF: 0.00910

Gnomad4 AMR AF: 0.0264

Gnomad4 ASJ AF: 0.0490

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0160

Gnomad4 FIN AF: 0.0852

Gnomad4 NFE AF: 0.0600

Gnomad4 OTH AF: 0.0294

Alfa AF: 0.0490 Hom.: 36

Bravo AF: 0.0348

Asia WGS AF: 0.0120 AC: 40 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated cardiomyopathy 1P Pathogenic:1 Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2008	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in 1000Genomes: 67/2178=3% -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

This variant is associated with the following publications: (PMID: 18241046, 24037902, 21167350) -

Lissencephaly 10 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 02, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	15
DANN	Benign	0.79

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: rs77186188; hg19: chr6-118869423;