rs1319380436

Positions:

• chr6-123278318-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006073.4(TRDN):​c.1567G>C​(p.Glu523Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000263 in 1,140,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E523D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000026 (0 hom.)
• Consequence: TRDN NM_006073.4 missense, splice_region
• Scores: Splicing: ADA: 0.7349
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.0630

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06265408).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRDN	NM_006073.4	c.1567G>C	p.Glu523Gln	missense_variant, splice_region_variant	26/41	ENST00000334268.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRDN	ENST00000334268.9	c.1567G>C	p.Glu523Gln	missense_variant, splice_region_variant	26/41	1	NM_006073.4	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000178 AC: 2 AN: 112294 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 59882

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000303

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000263 AC: 3 AN: 1140454 Hom.: 0 Cov.: 20 AF XY: 0.00000178 AC XY: 1 AN XY: 561902

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000701

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000213

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

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

Dec 26, 2022

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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 463669). This variant has not been reported in the literature in individuals affected with TRDN-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.03%). This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 523 of the TRDN protein (p.Glu523Gln). This variant also falls at the last nucleotide of exon 26, which is part of the consensus splice site for this exon. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 21, 2020

The c.1567G>C variant (also known as p.E523Q), located in coding exon 26 of the TRDN gene, results from a G to C substitution at nucleotide position 1567. The amino acid change results in glutamic acid to glutamine at codon 523, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 26, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is well conserved in available vertebrate species. This amino acid position is well conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. In addition, this alteration is predicted to be tolerated by in silico analysis. 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	0.12
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	21
DANN	Benign	0.77
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.46	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.014
Sift	Benign	0.069	T
Sift4G	Uncertain	0.046	D
Polyphen		0.0010	B
Vest4		0.25
MutPred		0.26		Gain of MoRF binding (P = 0.0312);
MVP		0.072
ClinPred		0.016	T
GERP RS		1.3
Varity_R		0.054
gMVP		0.0078

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.73
dbscSNV1_RF	Benign	0.61
SpliceAI score (max)		0.18		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1319380436; hg19: chr6-123599463;