NM_002667.5:c.*397T>G

Variant names:

• chr6-118559477-T-G
• rs12198461
• NM_002667.5:c.*397T>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002667.5(PLN):​c.*397T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.474 in 233,892 control chromosomes in the GnomAD database, including 27,328 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.46 (16895 hom., cov: 31)
  • Exomes 𝑓: 0.49 (10433 hom.)
• Consequence: PLN NM_002667.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.604
• Publications: 9 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: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• lissencephaly due to LIS1 mutation

  Inheritance: AD Classification: STRONG Submitted by: Illumina

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 6-118559477-T-G is Benign according to our data. Variant chr6-118559477-T-G is described in ClinVar as Benign. ClinVar VariationId is 355141.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.535 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLN	NM_002667.5	c.*397T>G		3_prime_UTR_variant	Exon 2 of 2	ENST00000357525.6	NP_002658.1
CEP85L	NM_001042475.3	c.1020+6052A>C		intron_variant	Intron 3 of 12	ENST00000368491.8	NP_001035940.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLN	ENST00000357525.6	c.*397T>G		3_prime_UTR_variant	Exon 2 of 2	1	NM_002667.5	ENSP00000350132.5
CEP85L	ENST00000368491.8	c.1020+6052A>C		intron_variant	Intron 3 of 12	1	NM_001042475.3	ENSP00000357477.3

Frequencies

GnomAD3 genomes AF: 0.465 AC: 70541 AN: 151834 Hom.: 16897 Cov.: 31

Gnomad AFR AF: 0.393

Gnomad AMI AF: 0.409

Gnomad AMR AF: 0.344

Gnomad ASJ AF: 0.446

Gnomad EAS AF: 0.302

Gnomad SAS AF: 0.486

Gnomad FIN AF: 0.521

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.540

Gnomad OTH AF: 0.437

GnomAD4 exome AF: 0.493 AC: 40420 AN: 81940 Hom.: 10433 Cov.: 0 AF XY: 0.485 AC XY: 20631 AN XY: 42552

African (AFR) AF: 0.356 AC: 504 AN: 1414

American (AMR) AF: 0.299 AC: 1135 AN: 3796

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 671 AN: 1604

East Asian (EAS) AF: 0.272 AC: 964 AN: 3542

South Asian (SAS) AF: 0.470 AC: 5011 AN: 10666

European-Finnish (FIN) AF: 0.523 AC: 9169 AN: 17522

Middle Eastern (MID) AF: 0.479 AC: 91 AN: 190

European-Non Finnish (NFE) AF: 0.531 AC: 21111 AN: 39722

Other (OTH) AF: 0.506 AC: 1764 AN: 3484

GnomAD4 genome AF: 0.464 AC: 70560 AN: 151952 Hom.: 16895 Cov.: 31 AF XY: 0.460 AC XY: 34137 AN XY: 74272

African (AFR) AF: 0.392 AC: 16255 AN: 41444

American (AMR) AF: 0.343 AC: 5234 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.446 AC: 1548 AN: 3470

East Asian (EAS) AF: 0.302 AC: 1565 AN: 5174

South Asian (SAS) AF: 0.486 AC: 2341 AN: 4816

European-Finnish (FIN) AF: 0.521 AC: 5492 AN: 10544

Middle Eastern (MID) AF: 0.571 AC: 168 AN: 294

European-Non Finnish (NFE) AF: 0.540 AC: 36666 AN: 67922

Other (OTH) AF: 0.436 AC: 920 AN: 2108

Alfa AF: 0.474 Hom.: 6081

Bravo AF: 0.445

Asia WGS AF: 0.372 AC: 1286 AN: 3460

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dilated cardiomyopathy 1P Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.4
DANN	Benign	0.58
PhyloP100		0.60
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12198461; hg19: chr6-118880640; COSMIC: COSV62645809;