6-118559477-T-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: Labcorp Genetics (formerly Invitae), G2P, ClinGen
• 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.

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.*397T>G		3_prime_UTR	Exon 2 of 2	NP_002658.1	P26678
	CEP85L	NM_001042475.3	MANE Select	c.1020+6052A>C		intron	N/A	NP_001035940.1	Q5SZL2-1
	CEP85L	NM_001178035.2		c.1029+6052A>C		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.*397T>G		3_prime_UTR	Exon 2 of 2	ENSP00000350132.5	P26678
	CEP85L	ENST00000368491.8	TSL:1 MANE Select	c.1020+6052A>C		intron	N/A	ENSP00000357477.3	Q5SZL2-1
	CEP85L	ENST00000434604.5	TSL:1	c.1029+6052A>C		intron	N/A	ENSP00000392131.1	A2A3P3

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Dilated cardiomyopathy 1P (1)

Computational scores

Source: dbNSFP v4.9

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;