Genetic Variant NM_001042475.3:c.1020+6809T>C (chr6-118558720-A-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001042475.3(CEP85L):c.1020+6809T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 607,592 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0036 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00045 ( 1 hom. )

Consequence

CEP85L
NM_001042475.3 intron

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.51

Publications

0 publications found

Variant links:

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]

CEP85L links:

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

PLN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 6-118558720-A-G is Benign according to our data. Variant chr6-118558720-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 675990.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00364 (554/152054) while in subpopulation AFR AF = 0.0127 (528/41452). AF 95% confidence interval is 0.0118. There are 3 homozygotes in GnomAd4. There are 261 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 554 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CEP85L	NM_001042475.3	MANE Select	c.1020+6809T>C	intron	N/A	NP_001035940.1	Q5SZL2-1
PLN	NM_002667.5	MANE Select	c.-97-105A>G	intron	N/A	NP_002658.1	P26678
CEP85L	NM_001178035.2		c.1029+6809T>C	intron	N/A	NP_001171506.1	Q5SZL2-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CEP85L	ENST00000368491.8	TSL:1 MANE Select	c.1020+6809T>C	intron	N/A	ENSP00000357477.3	Q5SZL2-1
PLN	ENST00000357525.6	TSL:1 MANE Select	c.-97-105A>G	intron	N/A	ENSP00000350132.5	P26678
CEP85L	ENST00000434604.5	TSL:1	c.1029+6809T>C	intron	N/A	ENSP00000392131.1	A2A3P3

Frequencies

GnomAD3 genomes

AF:

0.00362

AC:

550

AN:

151936

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0127

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00287

GnomAD4 exome

AF:

0.000446

AC:

203

AN:

455538

Hom.:

AF XY:

0.000397

AC XY:

AN XY:

244538

show subpopulations

African (AFR)

AF:

0.0123

AC:

154

AN:

12568

American (AMR)

AF:

0.00100

AC:

AN:

20900

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14160

East Asian (EAS)

AF:

0.00

AC:

AN:

30230

South Asian (SAS)

AF:

0.00

AC:

AN:

47058

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27928

Middle Eastern (MID)

AF:

0.000499

AC:

AN:

2004

European-Non Finnish (NFE)

AF:

0.00000364

AC:

AN:

274662

Other (OTH)

AF:

0.000999

AC:

AN:

26028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00364

AC:

554

AN:

152054

Hom.:

Cov.:

AF XY:

0.00351

AC XY:

261

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.0127

AC:

528

AN:

41452

American (AMR)

AF:

0.00118

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000208

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67988

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

105

131

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00277

Hom.:

Bravo

AF:

0.00404

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

5.5

(source)

DANN

Benign

0.82

PhyloP100

1.5

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over