rs6569336

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006073.4(TRDN):c.1408C>A(p.Leu470Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,422,180 control chromosomes in the GnomAD database, including 3,068 homozygotes. 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L470L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.085 ( 1786 hom., cov: 32)

Exomes 𝑓: 0.010 ( 1282 hom. )

Consequence

TRDN
NM_006073.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.0770

Publications

9 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 Gene-Disease associations (from GenCC):

catecholaminergic polymorphic ventricular tachycardia
Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
catecholaminergic polymorphic ventricular tachycardia 5
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
familial long QT syndrome
Inheritance: AR Classification: STRONG Submitted by: G2P
long QT syndrome
Inheritance: AR Classification: STRONG Submitted by: ClinGen

TRDN links:

LOC105377984 (HGNC:):

LOC105377984 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0048668683).

BP6

Variant 6-123337631-G-T is Benign according to our data. Variant chr6-123337631-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 227112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRDN	NM_006073.4 link	c.1408C>A	p.Leu470Met	missense_variant	Exon 22 of 41	ENST00000334268.9	NP_006064.2	Q13061-1
LOC105377984	XR_942947.3 link	n.214-1G>T		splice_acceptor_variant, intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9 link	c.1408C>A	p.Leu470Met	missense_variant	Exon 22 of 41	1	NM_006073.4	ENSP00000333984.5		Q13061-1

Frequencies

GnomAD3 genomes

AF:

0.0851

AC:

12923

AN:

151898

Hom.:

1783

Cov.:

show subpopulations

Gnomad AFR

AF:

0.289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0303

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00174

Gnomad SAS

AF:

0.0639

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00118

Gnomad OTH

AF:

0.0628

GnomAD2 exomes

AF:

0.0247

AC:

3225

AN:

130400

AF XY:

0.0240

show subpopulations

Gnomad AFR exome

AF:

0.275

Gnomad AMR exome

AF:

0.0128

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00121

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00145

Gnomad OTH exome

AF:

0.0121

GnomAD4 exome

AF:

0.0105

AC:

13318

AN:

1270164

Hom.:

1282

Cov.:

AF XY:

0.0112

AC XY:

7009

AN XY:

628308

show subpopulations

African (AFR)

AF:

0.277

AC:

7291

AN:

26360

American (AMR)

AF:

0.0154

AC:

411

AN:

26722

Ashkenazi Jewish (ASJ)

AF:

0.000216

AC:

AN:

23126

East Asian (EAS)

AF:

0.000686

AC:

AN:

32058

South Asian (SAS)

AF:

0.0577

AC:

3833

AN:

66412

European-Finnish (FIN)

AF:

0.0000215

AC:

AN:

46568

Middle Eastern (MID)

AF:

0.0149

AC:

AN:

4772

European-Non Finnish (NFE)

AF:

0.000556

AC:

551

AN:

991756

Other (OTH)

AF:

0.0216

AC:

1133

AN:

52390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

390

780

1169

1559

1949

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0852

AC:

12946

AN:

152016

Hom.:

1786

Cov.:

AF XY:

0.0821

AC XY:

6103

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.288

AC:

11949

AN:

41438

American (AMR)

AF:

0.0302

AC:

461

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00174

AC:

AN:

5174

South Asian (SAS)

AF:

0.0639

AC:

308

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10572

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00118

AC:

AN:

67974

Other (OTH)

AF:

0.0621

AC:

131

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

474

948

1421

1895

2369

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0326

Hom.:

1107

Bravo

AF:

0.0954

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.252

AC:

572

ESP6500EA

AF:

0.000800

AC:

ExAC

AF:

0.0460

AC:

1142

Asia WGS

AF:

0.0480

AC:

167

AN:

3470

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Leu470Met in exon 22 of TRDN: This variant is not expected to have clinical sign ificance because it has been identified in 25.2% (572/2268) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs6569336). -

Oct 03, 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. -

Feb 08, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 20, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jul 15, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.054

LIST_S2

Benign

0.37

MetaRNN

Benign

0.0049

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.69

PhyloP100

-0.077

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.16

REVEL

Benign

0.021

Sift

Uncertain

0.019

Sift4G

Benign

0.15

Polyphen

0.61

Vest4

0.064

ClinPred

0.0031

GERP RS

0.78

Varity_R

0.082

gMVP

0.0093

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs6569336

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over