chr6-123269854-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006073.4(TRDN):​c.1733C>A​(p.Pro578Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000348 in 1,610,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

TRDN
NM_006073.4 missense

Scores

1
1
17

Clinical Significance

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

Conservation

PhyloP100: 0.936
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 Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.07036367).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TRDNNM_006073.4 linkuse as main transcriptc.1733C>A p.Pro578Gln missense_variant 31/41 ENST00000334268.9 NP_006064.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TRDNENST00000334268.9 linkuse as main transcriptc.1733C>A p.Pro578Gln missense_variant 31/411 NM_006073.4 ENSP00000333984 A2Q13061-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
151884
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000295
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.0000325
AC:
8
AN:
246374
Hom.:
0
AF XY:
0.0000224
AC XY:
3
AN XY:
133654
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000627
Gnomad OTH exome
AF:
0.000168
GnomAD4 exome
AF:
0.0000357
AC:
52
AN:
1458524
Hom.:
0
Cov.:
30
AF XY:
0.0000400
AC XY:
29
AN XY:
725420
show subpopulations
Gnomad4 AFR exome
AF:
0.0000599
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:
0.0000378
Gnomad4 OTH exome
AF:
0.0000332
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
151884
Hom.:
0
Cov.:
32
AF XY:
0.0000270
AC XY:
2
AN XY:
74160
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000295
Gnomad4 OTH
AF:
0.000479
Alfa
AF:
0.0000995
Hom.:
1
Bravo
AF:
0.0000378
ExAC
AF:
0.0000331
AC:
4
EpiCase
AF:
0.000165
EpiControl
AF:
0.0000600

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), LabcorpJul 26, 2022This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 578 of the TRDN protein (p.Pro578Gln). This variant is present in population databases (rs761240477, gnomAD 0.007%). 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: 532338). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine 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
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 31, 2024The c.1733C>A (p.P578Q) alteration is located in exon 31 (coding exon 31) of the TRDN gene. This alteration results from a C to A substitution at nucleotide position 1733, causing the proline (P) at amino acid position 578 to be replaced by a glutamine (Q). 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
0.10
BayesDel_addAF
Benign
-0.36
T
BayesDel_noAF
Benign
-0.57
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Benign
0.099
T
Eigen
Benign
-0.33
Eigen_PC
Benign
-0.21
FATHMM_MKL
Benign
0.68
D
LIST_S2
Benign
0.47
T
M_CAP
Benign
0.0057
T
MetaRNN
Benign
0.070
T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
0.55
N
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-0.060
N
REVEL
Benign
0.0050
Sift
Pathogenic
0.0
D
Sift4G
Benign
0.061
T
Polyphen
0.29
B
Vest4
0.20
MVP
0.081
ClinPred
0.18
T
GERP RS
2.7
Varity_R
0.15
gMVP
0.016

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs761240477; hg19: chr6-123590999; API