rs201021891

Variant names:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2BP4_StrongBP6_Very_Strong

The NM_006073.4(TRDN):c.367G>A(p.Asp123Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000334 in 1,572,536 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00033 ( 1 hom. )

Consequence

TRDN
NM_006073.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:5

Conservation

PhyloP100: 3.85

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 links:

ENSG00000285691 (HGNC:):

ENSG00000285691 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.004431665).

BP6

Variant 6-123548478-C-T is Benign according to our data. Variant chr6-123548478-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 264130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRDN	NM_006073.4 link	c.367G>A	p.Asp123Asn	missense_variant	Exon 3 of 41	ENST00000334268.9	NP_006064.2	Q13061-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9 link	c.367G>A	p.Asp123Asn	missense_variant	Exon 3 of 41	1	NM_006073.4	ENSP00000333984.5		Q13061-1

Frequencies

GnomAD3 genomes

AF:

0.000336

AC:

AN:

151894

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

Gnomad ASJ

AF:

0.0124

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000442

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.000679

AC:

140

AN:

206190

Hom.:

AF XY:

0.000574

AC XY:

AN XY:

111460

show subpopulations

Gnomad AFR exome

AF:

0.0000790

Gnomad AMR exome

AF:

0.000182

Gnomad ASJ exome

AF:

0.0136

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000140

Gnomad OTH exome

AF:

0.00101

GnomAD4 exome

AF:

0.000334

AC:

475

AN:

1420642

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

237

AN XY:

704412

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000389

Gnomad4 ASJ exome

AF:

0.0140

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000586

Gnomad4 OTH exome

AF:

0.000854

GnomAD4 genome

AF:

0.000336

AC:

AN:

151894

Hom.:

Cov.:

AF XY:

0.000324

AC XY:

AN XY:

74174

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000657

Gnomad4 ASJ

AF:

0.0124

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000442

Gnomad4 OTH

AF:

0.00192

Alfa

AF:

0.000759

Hom.:

Bravo

AF:

0.000431

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000266

AC:

ESP6500EA

AF:

0.000486

AC:

ExAC

AF:

0.000399

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

May 22, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

This patient is a 14-year old female with a history of chronic dizziness and one episode of VT detected on Holter. She had an Arrhythmia and Cardiomyopathy Comprehensive Panel with the Invitae Laboratory. The following genes were evaluated for sequence changes and exonic deletions/duplications: ABCC9, ACTC1, ACTN2, AGL, AKAP9, ANK2, ANKRD1, BAG3, CACNA1C, CACNA2D1, CACNB2, CALM1, CALM2, CALM3, CALR3, CASQ2, CAV3, CHRM2, CRYAB, CSRP3, CTF1, CTNNA3, DES, DMD, DOLK, DSC2, DSG2, DSP, DTNA, EMD, EYA4, FHL1, FHL2, FKRP, FKTN, FLNC, GAA, GATA4, GATA6, GATAD1, GJA5, GLA, GPD1L, HCN4, ILK, JPH2, JUP, KCNA5, KCND3, KCNE1, KCNE2, KCNE3, KCNE5, KCNH2, KCNJ2, KCNJ5, KCNJ8, KCNK3, KCNQ1, LAMA4, LAMP2, LDB3, LMNA, LRRC10, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYL4, MYLK2, MYOM1, MYOZ2, MYPN, NEBL, NEXN, NKX2-5, NPPA, PDLIM3, PKP2, PLEKHM2, PLN, PRDM16, PRKAG2, RAF1, RANGRF, RBM20, RYR2, SCN10A, SCN1B, SCN2B, SCN3B, SCN4B, SCN5A, SGCD, SLC22A5, SLMAP, SNTA1, TAZ, TCAP, TGFB3, TMEM43, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TRDN, TRPM4, TTN, TTR, TXNRD2, VCL. Results indicate that two variants were detected: p.Asp123Asn (D123N; c.367G>A) in the TRDN gene p.Arg696Cys (c.2086C>T) in the MYOM1 gene We do not currently suspect that either of these is the cause of her episodes of dizziness and VT. p.Asp123Asn (D123N; c.367G>A) in exon 3 of the TRDN gene (NM_006073.3) Chromosome position 6:123869623 C / T The TRDN gene causes an autosomal recessive form of LQTS and CPVT. No second variant was reported in the patientâ€™s other TRDN allele. Invitae classifies p.Asp123Asn as a Variant of Uncertain Signficance (VUS). As of 5/22/2017 it has been reported to ClinVar as a VUS by Ambry, GeneDx, and Illumina as well. Based on the information reviewed below, including its high frequency among the Ashkenazi Jewish population, and the fact that it is not a truncating mutation, we classify it as a VUS, probably benign, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for diagnosis or predictive genetic testing. This variant has not previously been reported in the literature in association with disease. Typically, pathogenic TRDN variants are truncating (frameshift, splice site, or nonsense) rather than a missense variant such as this one. This is a nonconservative amino acid change, resulting in the replacement of a negatively-charged Aspartic Acid with a polar Asparagine. Aspartic Acid at this location is not conserved across ~100 vertebrate species for which we have data, and a Glutamic Acid (with similar properties) at this site is equally likely. The adjacent residues are also not conserved. There is currently no missense variation at nearby residues (+/- 10 amino acids) listed in ClinVar as Likely Pathogenic or Pathogenic. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Unknown"; AlignGVGD: "Class C0"). This variant was reported in 141 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Overall allele frequency 0.06%. Specifically, the variant was observed in 117/4,326 people with Ashkenazi Jewish ancestry (for the highest allele frequency: 1.35%), and also in 11/53,136 people with European (non-Finnish) ancestry for allele frequency 0.01%, as well as in 4 Latinos, 1 African-ancestry, and 8 â€œotherâ€ individuals. There are also 5 individuals with an in-frame deletion of Asp123 in gnomAD. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. Our patientâ€™s ancestry -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TRDN: BP4 -

Dec 16, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 31341780) -

Catecholaminergic polymorphic ventricular tachycardia 1;C3809536:Catecholaminergic polymorphic ventricular tachycardia 5

Benign:1

Apr 20, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 12, 2017

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

T;.;.;.

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.76

T;T;T;T

M_CAP

Benign

0.036

MetaRNN

Benign

0.0044

T;T;T;T

MetaSVM

Benign

-0.57

MutationAssessor

Uncertain

2.1

M;M;.;M

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.7

N;.;N;N

REVEL

Benign

0.18

Sift

Uncertain

0.0070

D;.;D;T

Sift4G

Benign

0.33

T;T;T;T

Polyphen

0.64

P;.;.;.

Vest4

0.17

MVP

0.49

ClinPred

0.022

GERP RS

5.1

Varity_R

0.16

gMVP

0.022

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over