rs766406818

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_006073.4(TRDN):c.1808G>C(p.Gly603Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000208 in 1,297,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000084 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

TRDN
NM_006073.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -2.09

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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.026840955).

BP6

Variant 6-123260635-C-G is Benign according to our data. Variant chr6-123260635-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 532357.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRDN	NM_006073.4 link	c.1808G>C	p.Gly603Ala	missense_variant	Exon 34 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.1808G>C	p.Gly603Ala	missense_variant	Exon 34 of 41	1	NM_006073.4	ENSP00000333984.5		Q13061-1

Frequencies

GnomAD3 genomes

AF:

0.0000840

AC:

AN:

95236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000166

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000246

AC:

AN:

81270

AF XY:

0.0000225

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000537

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000158

AC:

AN:

1202596

Hom.:

Cov.:

AF XY:

0.0000169

AC XY:

AN XY:

592862

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25080

American (AMR)

AF:

0.00

AC:

AN:

19090

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20000

East Asian (EAS)

AF:

0.00

AC:

AN:

31514

South Asian (SAS)

AF:

0.00

AC:

AN:

60310

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41324

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4056

European-Non Finnish (NFE)

AF:

0.0000200

AC:

AN:

952280

Other (OTH)

AF:

0.00

AC:

AN:

48942

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.412

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:

0.0000840

AC:

AN:

95236

Hom.:

Cov.:

AF XY:

0.0000650

AC XY:

AN XY:

46130

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22876

American (AMR)

AF:

0.00

AC:

AN:

8448

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2390

East Asian (EAS)

AF:

0.00

AC:

AN:

3194

South Asian (SAS)

AF:

0.00

AC:

AN:

2302

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5792

Middle Eastern (MID)

AF:

0.00

AC:

AN:

188

European-Non Finnish (NFE)

AF:

0.000166

AC:

AN:

48106

Other (OTH)

AF:

0.00

AC:

AN:

1220

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.531

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:

0.0000602

Hom.:

ExAC

AF:

0.0000423

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

May 12, 2020

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Catecholaminergic polymorphic ventricular tachycardia 1

Uncertain:1

Aug 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 603 of the TRDN protein (p.Gly603Ala). This variant is present in population databases (rs766406818, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with TRDN-related conditions. ClinVar contains an entry for this variant (Variation ID: 532357). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Benign:1

Apr 25, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.0070

(source)

DANN

Benign

0.080

DEOGEN2

Benign

0.095

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.39

M_CAP

Benign

0.0053

MetaRNN

Benign

0.027

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.81

PhyloP100

-2.1

PrimateAI

Benign

0.27

PROVEAN

Benign

0.24

REVEL

Benign

0.0020

Sift

Benign

0.26

Sift4G

Benign

0.30

Polyphen

0.0

Vest4

0.065

MVP

0.014

ClinPred

0.066

GERP RS

-2.8

Varity_R

0.035

gMVP

0.013

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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