6-123278318-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006073.4(TRDN):ā€‹c.1567G>Cā€‹(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 (ā˜…ā˜…). 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 š‘“: 0.0000026 ( 0 hom. )

Consequence

TRDN
NM_006073.4 missense, splice_region

Scores

1
18
Splicing: ADA: 0.7349
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.0630
Variant links:
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]

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ACMG classification

Classification made for transcript

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
TRDNNM_006073.4 linkuse as main transcriptc.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
TRDNENST00000334268.9 linkuse as main transcriptc.1567G>C p.Glu523Gln missense_variant, splice_region_variant 26/411 NM_006073.4 A2Q13061-1

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
show subpopulations
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
show subpopulations
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
LINK: link

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 26, 2022In 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 submitterclinical testingAmbry GeneticsAug 21, 2020The 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1319380436; hg19: chr6-123599463; API