6-123377897-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_006073.4(TRDN):c.1188A>G(p.Lys396Lys) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 1,470,594 control chromosomes in the GnomAD database, including 95,898 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 9543 hom., cov: 32)

Exomes 𝑓: 0.35 ( 86355 hom. )

Consequence

TRDN
NM_006073.4 splice_region, synonymous

Scores

Splicing: ADA: 0.002327

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.10

Publications

12 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 6-123377897-T-C is Benign according to our data. Variant chr6-123377897-T-C is described in ClinVar as Benign. ClinVar VariationId is 227106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.1 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.398 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRDN	NM_006073.4 link	c.1188A>G	p.Lys396Lys	splice_region_variant, synonymous_variant	Exon 17 of 41	ENST00000334268.9	NP_006064.2	Q13061-1
TRDN	NM_001251987.2 link	c.1191A>G	p.Lys397Lys	splice_region_variant, synonymous_variant	Exon 17 of 21		NP_001238916.1	A0A590UJV0Q8IVK2
TRDN	NM_001407315.1 link	c.1131A>G	p.Lys377Lys	splice_region_variant, synonymous_variant	Exon 16 of 20		NP_001394244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9 link	c.1188A>G	p.Lys396Lys	splice_region_variant, synonymous_variant	Exon 17 of 41	1	NM_006073.4	ENSP00000333984.5		Q13061-1
TRDN	ENST00000662930.1 link	c.1191A>G	p.Lys397Lys	splice_region_variant, synonymous_variant	Exon 17 of 21			ENSP00000499585.1		A0A590UJV0

Frequencies

GnomAD3 genomes

AF:

0.346

AC:

52611

AN:

151980

Hom.:

9526

Cov.:

show subpopulations

Gnomad AFR

AF:

0.338

Gnomad AMI

AF:

0.271

Gnomad AMR

AF:

0.406

Gnomad ASJ

AF:

0.401

Gnomad EAS

AF:

0.115

Gnomad SAS

AF:

0.161

Gnomad FIN

AF:

0.265

Gnomad MID

AF:

0.427

Gnomad NFE

AF:

0.378

Gnomad OTH

AF:

0.387

GnomAD2 exomes

AF:

0.333

AC:

52080

AN:

156336

AF XY:

0.323

show subpopulations

Gnomad AFR exome

AF:

0.345

Gnomad AMR exome

AF:

0.414

Gnomad ASJ exome

AF:

0.394

Gnomad EAS exome

AF:

0.119

Gnomad FIN exome

AF:

0.289

Gnomad NFE exome

AF:

0.389

Gnomad OTH exome

AF:

0.378

GnomAD4 exome

AF:

0.355

AC:

467949

AN:

1318496

Hom.:

86355

Cov.:

AF XY:

0.349

AC XY:

228237

AN XY:

654760

show subpopulations

African (AFR)

AF:

0.340

AC:

9966

AN:

29330

American (AMR)

AF:

0.411

AC:

14272

AN:

34704

Ashkenazi Jewish (ASJ)

AF:

0.395

AC:

9658

AN:

24474

East Asian (EAS)

AF:

0.140

AC:

4989

AN:

35734

South Asian (SAS)

AF:

0.176

AC:

13442

AN:

76212

European-Finnish (FIN)

AF:

0.287

AC:

13833

AN:

48146

Middle Eastern (MID)

AF:

0.367

AC:

1575

AN:

4288

European-Non Finnish (NFE)

AF:

0.377

AC:

380903

AN:

1010336

Other (OTH)

AF:

0.349

AC:

19311

AN:

55272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

11608

23215

34823

46430

58038

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11668

23336

35004

46672

58340

<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:

0.346

AC:

52661

AN:

152098

Hom.:

9543

Cov.:

AF XY:

0.336

AC XY:

24970

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.337

AC:

13999

AN:

41496

American (AMR)

AF:

0.406

AC:

6198

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.401

AC:

1393

AN:

3472

East Asian (EAS)

AF:

0.115

AC:

595

AN:

5184

South Asian (SAS)

AF:

0.161

AC:

777

AN:

4820

European-Finnish (FIN)

AF:

0.265

AC:

2805

AN:

10582

Middle Eastern (MID)

AF:

0.429

AC:

126

AN:

294

European-Non Finnish (NFE)

AF:

0.378

AC:

25697

AN:

67970

Other (OTH)

AF:

0.390

AC:

824

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1720

3440

5159

6879

8599

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

502

1004

1506

2008

2510

<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:

0.375

Hom.:

28711

Bravo

AF:

0.361

Asia WGS

AF:

0.192

AC:

670

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Apr 04, 2023

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

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

Lys396Lys in exon 17 of TRDN: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 36.4% (2890/7950) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs6901953). -

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

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 27, 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. -

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

Mar 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

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.90

PhyloP100

1.1

Mutation Taster

=54/46

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0023

dbscSNV1_RF

Benign

0.13

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

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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