rs755534468

Positions:

• chr6-123497195-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000334268.9(TRDN):​c.851C>G​(p.Pro284Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000107 in 1,396,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: TRDN ENST00000334268.9 missense, splice_region
• Scores: Splicing: ADA: 0.9350
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.11

Genes affected

TRDN (HGNC:12261): (triadin) This gene encodes an integral membrane protein found in skeletal and cardiac muscle. The encoded protein plays a role in skeletal muscle excitation-contraction coupling as part of the calcium release complex and is required for normal skeletal muscle strength. This protein indirectly links triads and microtubules in skeletal muscle. Mutations in this gene are associated with cardiac arrythmia syndrome and some variants in this gene may be associated with sudden cardiac death. [provided by RefSeq, May 2022]

TRDN-AS1 (HGNC:40592): (TRDN antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36280793).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRDN	NM_006073.4	c.851C>G	p.Pro284Arg	missense_variant, splice_region_variant	9/41	ENST00000334268.9	NP_006064.2
TRDN	NM_001251987.2	c.851C>G	p.Pro284Arg	missense_variant, splice_region_variant	9/21		NP_001238916.1
TRDN	NM_001256020.2	c.793+6524C>G		intron_variant			NP_001242949.1
TRDN	NM_001407315.1	c.793+6524C>G		intron_variant			NP_001394244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9	c.851C>G	p.Pro284Arg	missense_variant, splice_region_variant	9/41	1	NM_006073.4	ENSP00000333984	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000120 AC: 2 AN: 166958 Hom.: 0 AF XY: 0.0000112 AC XY: 1 AN XY: 89620

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000279

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000107 AC: 15 AN: 1396074 Hom.: 0 Cov.: 28 AF XY: 0.00000434 AC XY: 3 AN XY: 690492

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000130

Gnomad4 OTH exome AF: 0.0000174

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000838 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 21, 2022

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 284 of the TRDN protein (p.Pro284Arg). This variant is present in population databases (rs755534468, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with TRDN-related conditions. ClinVar contains an entry for this variant (Variation ID: 532386). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2017

The p.P284R variant (also known as c.851C>G), located in coding exon 9 of the TRDN gene, results from a C to G substitution at nucleotide position 851. The proline at codon 284 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.039	D
Polyphen		1.0	D
Vest4		0.32
MutPred		0.29		Gain of solvent accessibility (P = 0.0411);
MVP		0.48
ClinPred		0.64	D
GERP RS		6.0
Varity_R		0.39
gMVP		0.023

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.93
dbscSNV1_RF	Benign	0.65
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.27		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs755534468; hg19: chr6-123818340;