chr6-123271146-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_006073.4(TRDN):c.1713A>C(p.Glu571Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000228 in 1,534,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E571K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

TRDN
NM_006073.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 0.326

Publications

0 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008672982).

BP6

Variant 6-123271146-T-G is Benign according to our data. Variant chr6-123271146-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 415185. Variant chr6-123271146-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 415185. Variant chr6-123271146-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 415185. Variant chr6-123271146-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 415185. Variant chr6-123271146-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 415185. Variant chr6-123271146-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 415185. Variant chr6-123271146-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 415185. Variant chr6-123271146-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 415185. Variant chr6-123271146-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 415185. Variant chr6-123271146-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 415185. Variant chr6-123271146-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 415185. Variant chr6-123271146-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 415185. Variant chr6-123271146-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 415185. Variant chr6-123271146-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 415185. Variant chr6-123271146-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 415185. Variant chr6-123271146-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 415185. Variant chr6-123271146-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 415185. Variant chr6-123271146-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 415185. Variant chr6-123271146-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 415185. Variant chr6-123271146-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 415185. Variant chr6-123271146-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 415185. Variant chr6-123271146-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 415185. Variant chr6-123271146-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 415185. Variant chr6-123271146-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 415185. Variant chr6-123271146-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 415185. Variant chr6-123271146-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 415185. Variant chr6-123271146-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 415185. Variant chr6-123271146-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 415185. Variant chr6-123271146-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 415185. Variant chr6-123271146-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 415185. Variant chr6-123271146-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 415185. Variant chr6-123271146-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 415185. Variant chr6-123271146-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 415185.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00129 (196/152092) while in subpopulation AFR AF = 0.00458 (190/41526). AF 95% confidence interval is 0.00404. There are 0 homozygotes in GnomAd4. There are 101 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRDN	NM_006073.4 link	c.1713A>C	p.Glu571Asp	missense_variant	Exon 30 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.1713A>C	p.Glu571Asp	missense_variant	Exon 30 of 41	1	NM_006073.4	ENSP00000333984.5		Q13061-1

Frequencies

GnomAD3 genomes

AF:

0.00129

AC:

196

AN:

151974

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.000345

AC:

AN:

150848

AF XY:

0.000312

show subpopulations

Gnomad AFR exome

AF:

0.00530

Gnomad AMR exome

AF:

0.000178

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000163

Gnomad OTH exome

AF:

0.000237

GnomAD4 exome

AF:

0.000111

AC:

154

AN:

1382710

Hom.:

Cov.:

AF XY:

0.000103

AC XY:

AN XY:

682670

show subpopulations

African (AFR)

AF:

0.00443

AC:

136

AN:

30734

American (AMR)

AF:

0.000152

AC:

AN:

32988

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24466

East Asian (EAS)

AF:

0.00

AC:

AN:

36272

South Asian (SAS)

AF:

0.00

AC:

AN:

76654

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45994

Middle Eastern (MID)

AF:

0.000178

AC:

AN:

5608

European-Non Finnish (NFE)

AF:

9.32e-7

AC:

AN:

1072590

Other (OTH)

AF:

0.000192

AC:

AN:

57404

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00129

AC:

196

AN:

152092

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

101

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.00458

AC:

190

AN:

41526

American (AMR)

AF:

0.000197

AC:

AN:

15210

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67958

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000313

Hom.:

Bravo

AF:

0.00147

ESP6500AA

AF:

0.00311

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000214

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Feb 04, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 09, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Uncertain:1Benign:1

Sep 06, 2018

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. -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Catecholaminergic polymorphic ventricular tachycardia 5

Uncertain:1

Jun 06, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: BP4 supporting -

not specified

Benign:1

Dec 27, 2024

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TRDN c.1713A>C (p.Glu571Asp) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 150848 control chromosomes, predominantly at a frequency of 0.0053 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in TRDN causing Catecholaminergic Polymorphic Ventricular Tachycardia phenotype (0.0016). To our knowledge, no occurrence of c.1713A>C in individuals affected with Catecholaminergic Polymorphic Ventricular Tachycardia and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 415185). Based on the evidence outlined above, the variant was classified as likely benign. -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.083

Eigen

Benign

0.17

Eigen_PC

Benign

0.18

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.47

M_CAP

Benign

0.011

MetaRNN

Benign

0.0087

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

PhyloP100

0.33

PrimateAI

Uncertain

0.48

PROVEAN

Benign

0.020

REVEL

Benign

0.087

Sift

Pathogenic

0.0

Sift4G

Benign

0.23

Polyphen

1.0

Vest4

0.25

MutPred

0.26

Loss of sheet (P = 0.0315);

MVP

0.18

ClinPred

0.055

GERP RS

2.7

Varity_R

0.25

gMVP

0.010

Mutation Taster

=94/6

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