chr6-123503758-C-A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_006073.4(TRDN):​c.754G>T​(p.Asp252Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 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. D252G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

TRDN
NM_006073.4 missense

Scores

4
15

Clinical Significance

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

Conservation

PhyloP100: 0.689

Publications

1 publications found
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 was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.16783738).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TRDNNM_006073.4 linkc.754G>T p.Asp252Tyr missense_variant Exon 8 of 41 ENST00000334268.9 NP_006064.2 Q13061-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TRDNENST00000334268.9 linkc.754G>T p.Asp252Tyr missense_variant Exon 8 of 41 1 NM_006073.4 ENSP00000333984.5 Q13061-1

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
151960
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000161
AC:
4
AN:
248804
AF XY:
0.0000222
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000266
Gnomad OTH exome
AF:
0.000166
GnomAD4 exome
AF:
0.0000130
AC:
19
AN:
1461566
Hom.:
0
Cov.:
32
AF XY:
0.0000110
AC XY:
8
AN XY:
727056
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33476
American (AMR)
AF:
0.00
AC:
0
AN:
44704
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26128
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39678
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86250
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53384
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.0000153
AC:
17
AN:
1111820
Other (OTH)
AF:
0.0000331
AC:
2
AN:
60360
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.486
Heterozygous variant carriers
0
1
2
4
5
6
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
151960
Hom.:
0
Cov.:
31
AF XY:
0.0000135
AC XY:
1
AN XY:
74212
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41382
American (AMR)
AF:
0.00
AC:
0
AN:
15240
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5160
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4824
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10592
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000294
AC:
2
AN:
67974
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.00000756
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.0000248
AC:
3

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
Apr 07, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 252 of the TRDN protein (p.Asp252Tyr). This variant is present in population databases (rs749401047, 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: 463680). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). 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
Jul 17, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.D252Y variant (also known as c.754G>T), located in coding exon 8 of the TRDN gene, results from a G to T substitution at nucleotide position 754. The aspartic acid at codon 252 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species. 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
0.16
BayesDel_addAF
Benign
-0.094
T
BayesDel_noAF
Benign
-0.31
CADD
Benign
18
DANN
Uncertain
0.99
DEOGEN2
Benign
0.36
T;.;.
Eigen
Benign
-0.51
Eigen_PC
Benign
-0.62
FATHMM_MKL
Benign
0.085
N
LIST_S2
Benign
0.75
T;T;T
M_CAP
Benign
0.054
D
MetaRNN
Benign
0.17
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.2
L;L;.
PhyloP100
0.69
PrimateAI
Benign
0.23
T
PROVEAN
Uncertain
-3.2
D;.;D
REVEL
Benign
0.13
Sift
Uncertain
0.0080
D;.;D
Sift4G
Uncertain
0.0060
D;D;D
Polyphen
0.82
P;.;.
Vest4
0.24
MutPred
0.47
Gain of phosphorylation at D252 (P = 0.0143);Gain of phosphorylation at D252 (P = 0.0143);Gain of phosphorylation at D252 (P = 0.0143);
MVP
0.50
ClinPred
0.74
D
GERP RS
1.8
Varity_R
0.34
gMVP
0.011
Mutation Taster
=94/6
polymorphism

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

Other links and lift over

dbSNP: rs749401047; hg19: chr6-123824903; API