NM_002667.5:c.40_42delAGA

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+4 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 4 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_SupportingO7_ModerateO9_Supporting

The NM_002667.5(PLN):c.40_42delAGA (p.Arg14del) variant causes a conservative inframe deletion change. The variant results in an in-frame change. The variant allele was found at a cumulative frequency of 0.0000062 (AC=10) in the gnomAD database across 1,613,470 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000488. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 8.28). Variant has been reported in ClinVar as Pathogenic/Likely 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.

• 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: 233 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]

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, STRONG Submitted by: ClinGen, PanelApp Australia
• hypertrophic cardiomyopathy 18

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CEP85L (HGNC:21638): (centrosomal protein 85L) 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen
• lissencephaly due to LIS1 mutation

  Inheritance: AD Classification: STRONG Submitted by: Illumina

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 4 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Very rare in gnomAD (popmax AF <0.01%) — O3 supporting; GnomAD effective popmax AF = 0.000005 — very rare (O3 supporting [+1])
	O7Mutational hotspot or critical domain		Moderate: ≥10 same AA change, or strong functional domain signal; No cancerhotspots.org hit at this position; UniProt domain: 5 pathogenic, 1 benign (OR vs. background: 18.3).; ±8 AA neighbourhood: 4 pathogenic, 0 benign (OR vs. background: 45.0); Variant does not impact splicing — splice-hotspot path not applicable
	O9Protein length change in non-repeat region		In-frame indel in non-repetitive region, gene type unknown (O9 supporting); In-frame indel in non-repetitive region — gene: unknown gene type

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_002667.5. You can select a different transcript below to see updated classification 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	Prot: NP_002658.1 UniProt:
	CEP85L NM_001042475.3	MANE Select	c.1020+6570_1020+6572delCTT	intron	Intron 3 of 12	Prot: NP_001035940.1 UniProt:
	CEP85L NM_001178035.2		c.1029+6570_1029+6572delCTT	intron	Intron 4 of 13	Prot: NP_001171506.1 UniProt:

PLN NM_002667.5

MANE Select

HGVSc / HGVSpc.40_42delAGAp.Arg14del

Exon rankExon 2 of 2

conservative_inframe_deletion

Prot: NP_002658.1UniProt: Q5R352P26678

CEP85L NM_001042475.3

MANE Select

HGVSc / HGVSpc.1020+6570_1020+6572delCTT

Exon rankIntron 3 of 12

intron

Prot: NP_001035940.1UniProt: Q5SZL2-1

CEP85L NM_001178035.2

HGVSc / HGVSpc.1029+6570_1029+6572delCTT

Exon rankIntron 4 of 13

intron

Prot: NP_001171506.1UniProt: Q5SZL2-4

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PLN ENST00000357525.6	TSL:1MANE Select	c.40_42delAGA p.Arg14del	conservative_inframe_deletion	Exon 2 of 2	Prot: ENSP00000350132.5 UniProt:
	CEP85L ENST00000368491.8	TSL:1MANE Select	c.1020+6570_1020+6572delCTT	intron	Intron 3 of 12	Prot: ENSP00000357477.3 UniProt:
	CEP85L ENST00000434604.5	TSL:1	c.1029+6570_1029+6572delCTT	intron	Intron 4 of 8	Prot: ENSP00000392131.1 UniProt:

PLN ENST00000357525.6

TSL:1MANE Select

HGVSc / HGVSpc.40_42delAGAp.Arg14del

Exon rankExon 2 of 2

conservative_inframe_deletion

Prot: ENSP00000350132.5UniProt: P26678

CEP85L ENST00000368491.8

TSL:1MANE Select

HGVSc / HGVSpc.1020+6570_1020+6572delCTT

Exon rankIntron 3 of 12

intron

Prot: ENSP00000357477.3UniProt: Q5SZL2-1

CEP85L ENST00000434604.5

TSL:1

HGVSc / HGVSpc.1029+6570_1029+6572delCTT

Exon rankIntron 4 of 8

intron

Prot: ENSP00000392131.1UniProt: A2A3P3

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000131	AC:2	Hom:0	AN:152178	Cov:32
GnomAD2 exomes	AF: 0.00000398	AC:1	Hom:	AN:251122	Cov:
GnomAD4 exome	AF: 0.00000547	AC:8	Hom:0	AN:1461292	Cov:
GnomAD4 genome	AF: 0.0000131	AC:2	Hom:0	AN:152178	Cov:32
TOPMed (Bravo)	AF: 0.00000756	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000445	AC:1	Hom:0	AN:22458	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.00	0	28420	0.0000347	1	28844
Epi25(Epilepsy)	0.00	0	41958	0.0000150	1	66888
SCHEMA(Schizophrenia)	0.00	0	113152	0.0000105	2	190650

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

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

Algorithm	Calibrated pred.	Score	Prediction
Mutation Taster	N/A	42/58	disease causing (ClinVar)
PhyloP100	Pathogenic	8.3

Showing 2 of 2 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 1 of 1 scores

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs397516784;

hg19: chr6-118880119;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar