chr6-123393633-C-T

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.1096G>A(p.Ala366Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00206 in 1,604,516 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. A366A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.012 ( 34 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 37 hom. )

Consequence

TRDN
NM_006073.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.232

Publications

8 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 links:

TRDN-AS1 (HGNC:40592): (TRDN antisense RNA 1)

TRDN-AS1 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=0.0032596886).

BP6

Variant 6-123393633-C-T is Benign according to our data. Variant chr6-123393633-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0115 (1754/152010) while in subpopulation AFR AF = 0.0397 (1647/41482). AF 95% confidence interval is 0.0381. There are 34 homozygotes in GnomAd4. There are 840 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 34 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRDN	NM_006073.4 link	c.1096G>A	p.Ala366Thr	missense_variant	Exon 13 of 41	ENST00000334268.9	NP_006064.2	Q13061-1
TRDN	NM_001251987.2 link	c.1099G>A	p.Ala367Thr	missense_variant	Exon 13 of 21		NP_001238916.1	A0A590UJV0Q8IVK2
TRDN	NM_001407315.1 link	c.1039G>A	p.Ala347Thr	missense_variant	Exon 12 of 20		NP_001394244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TRDN	ENST00000334268.9 link	c.1096G>A	p.Ala366Thr	missense_variant	Exon 13 of 41	1	NM_006073.4	ENSP00000333984.5	Q13061-1
TRDN	ENST00000662930.1 link	c.1099G>A	p.Ala367Thr	missense_variant	Exon 13 of 21			ENSP00000499585.1	A0A590UJV0
TRDN-AS1	ENST00000587106.6 link	n.55+4158C>T		intron_variant	Intron 1 of 8	5

Frequencies

GnomAD3 genomes

AF:

0.0115

AC:

1754

AN:

151896

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0398

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00485

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000416

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000442

Gnomad OTH

AF:

0.0134

GnomAD2 exomes

AF:

0.00257

AC:

606

AN:

236116

AF XY:

0.00207

show subpopulations

Gnomad AFR exome

AF:

0.0382

Gnomad AMR exome

AF:

0.00156

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000567

Gnomad OTH exome

AF:

0.00104

GnomAD4 exome

AF:

0.00107

AC:

1553

AN:

1452506

Hom.:

Cov.:

AF XY:

0.000937

AC XY:

676

AN XY:

721798

show subpopulations

African (AFR)

AF:

0.0389

AC:

1295

AN:

33260

American (AMR)

AF:

0.00164

AC:

AN:

43790

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25794

East Asian (EAS)

AF:

0.00

AC:

AN:

39568

South Asian (SAS)

AF:

0.0000589

AC:

AN:

84844

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52786

Middle Eastern (MID)

AF:

0.000696

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.0000316

AC:

AN:

1106788

Other (OTH)

AF:

0.00237

AC:

142

AN:

59932

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

136

205

273

341

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<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:

0.0115

AC:

1754

AN:

152010

Hom.:

Cov.:

AF XY:

0.0113

AC XY:

840

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.0397

AC:

1647

AN:

41482

American (AMR)

AF:

0.00485

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.000417

AC:

AN:

4796

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000442

AC:

AN:

67940

Other (OTH)

AF:

0.0133

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

172

258

344

430

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00436

Hom.:

Bravo

AF:

0.0125

ESP6500AA

AF:

0.0370

AC:

133

ESP6500EA

AF:

0.000123

AC:

ExAC

AF:

0.00315

AC:

380

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Oct 06, 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 25, 2024

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

Significance:Likely 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

- -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ala366Thr in exon 13 of TRDN: This variant is not expected to have clinical sign ificance because it has been identified in 3.7% (133/3592) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs35047281). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Jul 27, 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

Aug 23, 2020

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

0.063

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.48

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.070

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.40

MetaRNN

Benign

0.0033

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.20

PhyloP100

-0.23

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.21

REVEL

Benign

0.020

Sift

Benign

0.88

Sift4G

Benign

0.65

Polyphen

0.0010

Vest4

0.14

MVP

0.014

ClinPred

0.0011

GERP RS

0.88

Varity_R

0.030

gMVP

0.0089

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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