rs397516784

Variant names:

• chr6-118558956-TAAG-T
• rs397516784
• NM_002667.5:c.40_42delAGA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 15P and 4B. PS3 PM1 PM4_Supporting PP5_Very_Strong BS2

The NM_002667.5(PLN):​c.40_42delAGA​(p.Arg14del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,470 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000061240: Multiple functional studies, including mouse models, all support that the Arg14del variant impacts protein function (Haghighi 2006, Ceholski 2012 a, Ceholski 2012b, Haghighi 2012)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R14R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: PLN NM_002667.5 conservative_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:21 U:1
• Conservation: PhyloP100: 8.28
• Publications: 198 publications found

Genes affected

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]

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 Gene-Disease associations (from GenCC):

• lissencephaly 10

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• lissencephaly due to LIS1 mutation

  Inheritance: AD Classification: STRONG Submitted by: Illumina

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000061240: Multiple functional studies, including mouse models, all support that the Arg14del variant impacts protein function (Haghighi 2006, Ceholski 2012 a, Ceholski 2012b, Haghighi 2012).; SCV000236300: An in vitro functional study reported that R14del is a partial inhibitor of the sarcoplasmic reticulum calcium pump, and that it inhibits the phospholamban-protein kinase A interaction (Ceholski et al., 2012).; SCV000280420: Multiple functional studies, including mouse models, all support that the Arg14del variant impacts protein function (Haghighi 2006, Ceholski 2012a, Ceholski 2012b, Haghighi 2012).; SCV003802801: "In-vitro cell culture-based functional studies have shown that this variant results in the inhibition of SERCA, which is an important ATP-dependent calcium pump in the sarcoplasmic reticulum, and in-vivo studies have shown that transgenic mice that express this variant in the heart recapitulate the human cardiac phenotype." PMID:16432188; PMID:22155237; PMID:22427649; SCV000287496: Experimental studies have shown that this variant affects PLN function (PMID: 16432188, 22155237, 22707725).; SCV002557137: Functional analysis has shown that this variant has a dominant negative effect and results in sarcoplasmic reticulum Ca2+-ATPase inhibition. Additionally, transgenic mice develop DCM, abnormal histopathology and suffer premature death (PMID: 16432188).; SCV000318486: Functional assays have demonstrated that this alteration disrupts protein function and leads to dominant negative effects (Haghighi K et al. Proc Natl Acad Sci. U.S.A. 2006;103(5):1388-93; Haghighi K et al. J Mol Cell Cardiol. 2012;52(3):773-82; Ceholski D et al. J Biol Chem. 2012;287(32):26596-605; Ceholski DK et al. J Biol Chem. 2012;287(20):16521-9).; SCV006076320: Multiple functional studies, including mouse models, have demonstrated that the p.Arg14del variant has a deleterious impact on protein function (PMID:22707725; PMID:22155237; PMID:27450564).
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_002667.5
• PM4: Nonframeshift variant in NON repetitive region in NM_002667.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 6-118558956-TAAG-T is Pathogenic according to our data. Variant chr6-118558956-TAAG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 44580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002667.5. 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
	PLN	NM_002667.5	MANE Select	c.40_42delAGA	p.Arg14del	conservative_inframe_deletion	Exon 2 of 2	NP_002658.1	P26678
	CEP85L	NM_001042475.3	MANE Select	c.1020+6570_1020+6572delCTT		intron	N/A	NP_001035940.1	Q5SZL2-1
	CEP85L	NM_001178035.2		c.1029+6570_1029+6572delCTT		intron	N/A	NP_001171506.1	Q5SZL2-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLN	ENST00000357525.6	TSL:1 MANE Select	c.40_42delAGA	p.Arg14del	conservative_inframe_deletion	Exon 2 of 2	ENSP00000350132.5	P26678
	CEP85L	ENST00000368491.8	TSL:1 MANE Select	c.1020+6570_1020+6572delCTT		intron	N/A	ENSP00000357477.3	Q5SZL2-1
	CEP85L	ENST00000434604.5	TSL:1	c.1029+6570_1029+6572delCTT		intron	N/A	ENSP00000392131.1	A2A3P3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251122 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461292 Hom.: 0 AF XY: 0.00000688 AC XY: 5 AN XY: 727016

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111488

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74344

African (AFR) AF: 0.00 AC: 0 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	not provided (7)
6	-	-	Dilated cardiomyopathy 1P (6)
2	-	-	Cardiomyopathy (2)
1	1	-	Primary dilated cardiomyopathy (2)
1	-	-	Arrhythmogenic right ventricular dysplasia 9 (1)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Hypertrophic cardiomyopathy 18 (1)
1	-	-	PLN-related cardiomyopathy (1)
1	-	-	SUDDEN INFANT DEATH SYNDROME (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.3
Mutation Taster		=42/58	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs397516784;

hg19: chr6-118880119;