rs192289289

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006073.4(TRDN):c.403G>A(p.Glu135Lys) variant causes a missense change. The variant allele was found at a frequency of 0.01 in 1,458,352 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts 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. E135E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0085 ( 6 hom., cov: 32)

Exomes 𝑓: 0.010 ( 82 hom. )

Consequence

TRDN
NM_006073.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.76

Publications

10 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:

ENSG00000285691 (HGNC:):

ENSG00000285691 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=0.008121401).

BP6

Variant 6-123547361-C-T is Benign according to our data. Variant chr6-123547361-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00849 (1289/151898) while in subpopulation NFE AF = 0.0148 (1005/67906). AF 95% confidence interval is 0.014. There are 6 homozygotes in GnomAd4. There are 580 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRDN	NM_006073.4 link	c.403G>A	p.Glu135Lys	missense_variant	Exon 4 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.403G>A	p.Glu135Lys	missense_variant	Exon 4 of 41	1	NM_006073.4	ENSP00000333984.5		Q13061-1

Frequencies

GnomAD3 genomes

AF:

0.00849

AC:

1289

AN:

151780

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00285

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00440

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00674

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0148

Gnomad OTH

AF:

0.00719

GnomAD2 exomes

AF:

0.00692

AC:

782

AN:

113040

AF XY:

0.00690

show subpopulations

Gnomad AFR exome

AF:

0.00272

Gnomad AMR exome

AF:

0.00160

Gnomad ASJ exome

AF:

0.000435

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00790

Gnomad NFE exome

AF:

0.0119

Gnomad OTH exome

AF:

0.00695

GnomAD4 exome

AF:

0.0102

AC:

13360

AN:

1306454

Hom.:

Cov.:

AF XY:

0.00992

AC XY:

6382

AN XY:

643240

show subpopulations

African (AFR)

AF:

0.00165

AC:

AN:

27244

American (AMR)

AF:

0.00163

AC:

AN:

23350

Ashkenazi Jewish (ASJ)

AF:

0.000388

AC:

AN:

23192

East Asian (EAS)

AF:

0.00

AC:

AN:

32766

South Asian (SAS)

AF:

0.00155

AC:

AN:

62666

European-Finnish (FIN)

AF:

0.00818

AC:

394

AN:

48152

Middle Eastern (MID)

AF:

0.00185

AC:

AN:

5416

European-Non Finnish (NFE)

AF:

0.0120

AC:

12377

AN:

1029466

Other (OTH)

AF:

0.00720

AC:

390

AN:

54202

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.404

Heterozygous variant carriers

497

994

1492

1989

2486

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

468

936

1404

1872

2340

<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:

0.00849

AC:

1289

AN:

151898

Hom.:

Cov.:

AF XY:

0.00781

AC XY:

580

AN XY:

74224

show subpopulations

African (AFR)

AF:

0.00285

AC:

118

AN:

41460

American (AMR)

AF:

0.00440

AC:

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00166

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00674

AC:

AN:

10534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0148

AC:

1005

AN:

67906

Other (OTH)

AF:

0.00712

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

141

211

282

352

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<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:

0.0110

Hom.:

Bravo

AF:

0.00763

TwinsUK

AF:

0.0111

AC:

ALSPAC

AF:

0.0163

AC:

ESP6500AA

AF:

0.00294

AC:

ESP6500EA

AF:

0.00991

AC:

ExAC

AF:

0.00360

AC:

373

Asia WGS

AF:

0.000584

AC:

AN:

3440

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

May 14, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Glu135Lys in exon 4 of TRDN: This variant is not expected to have clinical sig nificance because it has been identified in 1.3% (118/8804) of European chromoso mes including 1 homozygous individual by the Exome Aggregation Consortium (http: //exac.broadinstitute.org/; dbSNP rs192289289). -

Apr 10, 2023

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

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

- -

Sep 28, 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. -

not provided

Benign:1

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TRDN: BS1, BS2 -

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

Apr 22, 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

Oct 10, 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

0.12

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

T;.;.;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.88

D;D;D;D

MetaRNN

Benign

0.0081

T;T;T;T

MetaSVM

Benign

-0.60

MutationAssessor

Uncertain

2.1

M;M;.;M

PhyloP100

3.8

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.1

N;.;N;N

REVEL

Benign

0.25

Sift

Uncertain

0.0070

D;.;D;D

Sift4G

Benign

0.32

T;T;T;T

Polyphen

1.0

D;.;.;.

Vest4

0.29

MVP

0.68

ClinPred

0.0062

GERP RS

5.7

Varity_R

0.22

gMVP

0.023

Mutation Taster

=97/3

polymorphism

(source)

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

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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