6-123366143-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006073.4(TRDN):​c.1313T>A​(p.Ile438Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00271 in 1,612,394 control chromosomes in the GnomAD database, including 140 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I438S) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0030 ( 12 hom., cov: 32)
Exomes 𝑓: 0.0027 ( 128 hom. )

Consequence

TRDN
NM_006073.4 missense

Scores

1
17

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.38
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 Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.002306044).
BP6
Variant 6-123366143-A-T is Benign according to our data. Variant chr6-123366143-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 227109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-123366143-A-T is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0679 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TRDNNM_006073.4 linkc.1313T>A p.Ile438Asn missense_variant Exon 20 of 41 ENST00000334268.9 NP_006064.2 Q13061-1
TRDNNM_001251987.2 linkc.1316T>A p.Ile439Asn missense_variant Exon 20 of 21 NP_001238916.1 A0A590UJV0Q8IVK2
TRDNNM_001407315.1 linkc.1256T>A p.Ile419Asn missense_variant Exon 19 of 20 NP_001394244.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TRDNENST00000334268.9 linkc.1313T>A p.Ile438Asn missense_variant Exon 20 of 41 1 NM_006073.4 ENSP00000333984.5 Q13061-1
TRDNENST00000662930.1 linkc.1316T>A p.Ile439Asn missense_variant Exon 20 of 21 ENSP00000499585.1 A0A590UJV0

Frequencies

GnomAD3 genomes
AF:
0.00304
AC:
463
AN:
152110
Hom.:
12
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000193
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000916
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.0741
Gnomad SAS
AF:
0.00870
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00430
GnomAD3 exomes
AF:
0.00693
AC:
1719
AN:
248196
Hom.:
54
AF XY:
0.00680
AC XY:
916
AN XY:
134654
show subpopulations
Gnomad AFR exome
AF:
0.0000647
Gnomad AMR exome
AF:
0.000146
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0811
Gnomad SAS exome
AF:
0.00749
Gnomad FIN exome
AF:
0.0000465
Gnomad NFE exome
AF:
0.0000711
Gnomad OTH exome
AF:
0.00432
GnomAD4 exome
AF:
0.00268
AC:
3907
AN:
1460166
Hom.:
128
Cov.:
37
AF XY:
0.00280
AC XY:
2035
AN XY:
726346
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000157
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.0722
Gnomad4 SAS exome
AF:
0.00781
Gnomad4 FIN exome
AF:
0.0000188
Gnomad4 NFE exome
AF:
0.0000450
Gnomad4 OTH exome
AF:
0.00519
GnomAD4 genome
AF:
0.00305
AC:
464
AN:
152228
Hom.:
12
Cov.:
32
AF XY:
0.00356
AC XY:
265
AN XY:
74420
show subpopulations
Gnomad4 AFR
AF:
0.000241
Gnomad4 AMR
AF:
0.000915
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.0740
Gnomad4 SAS
AF:
0.00870
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00425
Alfa
AF:
0.0000187
Hom.:
111556
ExAC
AF:
0.00695
AC:
839
EpiCase
AF:
0.0000546
EpiControl
AF:
0.00

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
Oct 29, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jun 11, 2015
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

p.Ile438Asn in exon 20 of TRDN: This variant is not expected to have clinical si gnificance it has been identified in 8.1% (693/8588) of East Asian chromosomes, including 21 homozygotes, by the Exome Aggregation Consortium (ExAC, http://exac .broadinstitute.org; dbSNP rs2873479). -

-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Oct 12, 2016
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

TRDN-related disorder Benign:1
Apr 09, 2019
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1
Feb 02, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1
Jun 09, 2015
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Catecholaminergic polymorphic ventricular tachycardia 5 Benign:1
Nov 09, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.069
BayesDel_addAF
Benign
-0.72
T
BayesDel_noAF
Benign
-0.74
CADD
Benign
19
DANN
Benign
0.78
DEOGEN2
Benign
0.063
T
Eigen
Benign
-0.82
Eigen_PC
Benign
-0.63
FATHMM_MKL
Benign
0.56
D
LIST_S2
Benign
0.35
T
MetaRNN
Benign
0.0023
T
MetaSVM
Benign
-0.93
T
MutationAssessor
Benign
0.0
N
PrimateAI
Benign
0.36
T
PROVEAN
Benign
0.45
N
REVEL
Benign
0.072
Sift
Uncertain
0.0080
D
Sift4G
Benign
0.49
T
Polyphen
0.0
B
Vest4
0.088
MVP
0.055
ClinPred
0.027
T
GERP RS
4.7
Varity_R
0.087
gMVP
0.0033

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs2873479; hg19: chr6-123687288; API