6-118558626-TACACACACACACACACACAC-TACACACACACACACACACACACACACACAC

Variant names:

• chr6-118558626-T-TACACACACAC
• rs371775061
• NM_001042475.3:c.1020+6893_1020+6902dupGTGTGTGTGT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001042475.3(CEP85L):​c.1020+6893_1020+6902dupGTGTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.015 (6 hom., cov: 0)
• Consequence: CEP85L NM_001042475.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.379
• Publications: 0 publications found

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]

PLN Gene-Disease associations (from GenCC):

• dilated cardiomyopathy 1P

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• intrinsic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 18

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0153 (1710/111450) while in subpopulation SAS AF = 0.0322 (84/2610). AF 95% confidence interval is 0.0266. There are 6 homozygotes in GnomAd4. There are 787 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1710 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042475.3. 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
	CEP85L	NM_001042475.3	MANE Select	c.1020+6893_1020+6902dupGTGTGTGTGT		intron	N/A	NP_001035940.1	Q5SZL2-1
	PLN	NM_002667.5	MANE Select	c.-97-173_-97-164dupCACACACACA		intron	N/A	NP_002658.1	P26678
	CEP85L	NM_001178035.2		c.1029+6893_1029+6902dupGTGTGTGTGT		intron	N/A	NP_001171506.1	Q5SZL2-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP85L	ENST00000368491.8	TSL:1 MANE Select	c.1020+6902_1020+6903insGTGTGTGTGT		intron	N/A	ENSP00000357477.3	Q5SZL2-1
	PLN	ENST00000357525.6	TSL:1 MANE Select	c.-97-199_-97-198insACACACACAC		intron	N/A	ENSP00000350132.5	P26678
	CEP85L	ENST00000434604.5	TSL:1	c.1029+6902_1029+6903insGTGTGTGTGT		intron	N/A	ENSP00000392131.1	A2A3P3

Frequencies

GnomAD3 genomes AF: 0.0153 AC: 1705 AN: 111390 Hom.: 6 Cov.: 0

Gnomad AFR AF: 0.0106

Gnomad AMI AF: 0.0271

Gnomad AMR AF: 0.0144

Gnomad ASJ AF: 0.0279

Gnomad EAS AF: 0.00374

Gnomad SAS AF: 0.0308

Gnomad FIN AF: 0.00314

Gnomad MID AF: 0.0313

Gnomad NFE AF: 0.0184

Gnomad OTH AF: 0.0210

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0153 AC: 1710 AN: 111450 Hom.: 6 Cov.: 0 AF XY: 0.0151 AC XY: 787 AN XY: 52156

African (AFR) AF: 0.0106 AC: 326 AN: 30814

American (AMR) AF: 0.0143 AC: 159 AN: 11120

Ashkenazi Jewish (ASJ) AF: 0.0279 AC: 80 AN: 2864

East Asian (EAS) AF: 0.00376 AC: 15 AN: 3992

South Asian (SAS) AF: 0.0322 AC: 84 AN: 2610

European-Finnish (FIN) AF: 0.00314 AC: 15 AN: 4774

Middle Eastern (MID) AF: 0.0340 AC: 7 AN: 206

European-Non Finnish (NFE) AF: 0.0184 AC: 971 AN: 52836

Other (OTH) AF: 0.0221 AC: 33 AN: 1496

Alfa AF: 0.00 Hom.: 143

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.38
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs371775061; hg19: chr6-118879789;