6-118558626-TACACACACACACACACACAC-TACACACACACACACACACACACACACACACACAC

Variant names:

• chr6-118558626-T-TACACACACACACAC
• rs371775061
• NM_001042475.3:c.1020+6889_1020+6902dupGTGTGTGTGTGTGT

Variant summary

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

The NM_001042475.3(CEP85L):​c.1020+6889_1020+6902dupGTGTGTGTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.00056 (0 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 = 0.000555 (62/111654) while in subpopulation SAS AF = 0.00191 (5/2616). AF 95% confidence interval is 0.000753. There are 0 homozygotes in GnomAd4. There are 32 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 62 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+6889_1020+6902dupGTGTGTGTGTGTGT		intron	N/A	NP_001035940.1	Q5SZL2-1
	PLN	NM_002667.5	MANE Select	c.-97-177_-97-164dupCACACACACACACA		intron	N/A	NP_002658.1	P26678
	CEP85L	NM_001178035.2		c.1029+6889_1029+6902dupGTGTGTGTGTGTGT		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+6903insGTGTGTGTGTGTGT		intron	N/A	ENSP00000357477.3	Q5SZL2-1
	PLN	ENST00000357525.6	TSL:1 MANE Select	c.-97-199_-97-198insACACACACACACAC		intron	N/A	ENSP00000350132.5	P26678
	CEP85L	ENST00000434604.5	TSL:1	c.1029+6902_1029+6903insGTGTGTGTGTGTGT		intron	N/A	ENSP00000392131.1	A2A3P3

Frequencies

GnomAD3 genomes AF: 0.000538 AC: 60 AN: 111592 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000617

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000449

Gnomad ASJ AF: 0.000348

Gnomad EAS AF: 0.000998

Gnomad SAS AF: 0.00190

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000453

Gnomad OTH AF: 0.00135

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

GnomAD4 genome AF: 0.000555 AC: 62 AN: 111654 Hom.: 0 Cov.: 0 AF XY: 0.000613 AC XY: 32 AN XY: 52238

African (AFR) AF: 0.000680 AC: 21 AN: 30862

American (AMR) AF: 0.000449 AC: 5 AN: 11142

Ashkenazi Jewish (ASJ) AF: 0.000348 AC: 1 AN: 2874

East Asian (EAS) AF: 0.00100 AC: 4 AN: 3994

South Asian (SAS) AF: 0.00191 AC: 5 AN: 2616

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4776

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 208

European-Non Finnish (NFE) AF: 0.000453 AC: 24 AN: 52942

Other (OTH) AF: 0.00133 AC: 2 AN: 1502

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

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;