6-123393666-C-A

Variant summary

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

The NM_006073.4(TRDN):​c.1063G>T​(p.Ala355Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000206 in 1,454,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

TRDN
NM_006073.4 missense

Scores

19

Clinical Significance

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

Conservation

PhyloP100: -0.498
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]
TRDN-AS1 (HGNC:40592): (TRDN antisense RNA 1)

Genome browser will be placed here

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=0.015891671).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TRDNNM_006073.4 linkc.1063G>T p.Ala355Ser missense_variant Exon 13 of 41 ENST00000334268.9 NP_006064.2 Q13061-1
TRDNNM_001251987.2 linkc.1066G>T p.Ala356Ser missense_variant Exon 13 of 21 NP_001238916.1 A0A590UJV0Q8IVK2
TRDNNM_001407315.1 linkc.1006G>T p.Ala336Ser missense_variant Exon 12 of 20 NP_001394244.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TRDNENST00000334268.9 linkc.1063G>T p.Ala355Ser missense_variant Exon 13 of 41 1 NM_006073.4 ENSP00000333984.5 Q13061-1
TRDNENST00000662930.1 linkc.1066G>T p.Ala356Ser missense_variant Exon 13 of 21 ENSP00000499585.1 A0A590UJV0
TRDN-AS1ENST00000587106.6 linkn.55+4191C>A intron_variant Intron 1 of 8 5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000673
AC:
16
AN:
237568
Hom.:
0
AF XY:
0.0000776
AC XY:
10
AN XY:
128836
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000480
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000206
AC:
30
AN:
1454222
Hom.:
0
Cov.:
30
AF XY:
0.0000263
AC XY:
19
AN XY:
722812
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000410
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000253
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000812
Gnomad4 OTH exome
AF:
0.0000333
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.0000113
ExAC
AF:
0.0000663
AC:
8

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
Jul 10, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 355 of the TRDN protein (p.Ala355Ser). This variant is present in population databases (rs776657049, gnomAD 0.05%). 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: 660929). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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
Jan 16, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1063G>T (p.A355S) alteration is located in exon 13 (coding exon 13) of the TRDN gene. This alteration results from a G to T substitution at nucleotide position 1063, causing the alanine (A) at amino acid position 355 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.084
BayesDel_addAF
Benign
-0.48
T
BayesDel_noAF
Benign
-0.59
CADD
Benign
14
DANN
Benign
0.86
DEOGEN2
Benign
0.089
T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.056
N
LIST_S2
Benign
0.38
T
M_CAP
Benign
0.028
D
MetaRNN
Benign
0.016
T
MetaSVM
Benign
-1.2
T
MutationAssessor
Benign
0.34
N
PrimateAI
Benign
0.26
T
PROVEAN
Benign
-0.17
N
REVEL
Benign
0.048
Sift
Benign
0.27
T
Sift4G
Benign
0.60
T
Polyphen
0.0080
B
Vest4
0.15
MutPred
0.20
Gain of phosphorylation at A355 (P = 0.0137);
MVP
0.076
ClinPred
0.030
T
GERP RS
-5.9
Varity_R
0.056
gMVP
0.011

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs776657049; hg19: chr6-123714811; API