6-123548571-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006073.4(TRDN):c.274G>A(p.Val92Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,555,512 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0066 ( 15 hom., cov: 31)

Exomes 𝑓: 0.00063 ( 13 hom. )

Consequence

TRDN
NM_006073.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.19

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:

ENSG00000285691 (HGNC:):

ENSG00000285691 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003935635).

BP6

Variant 6-123548571-C-T is Benign according to our data. Variant chr6-123548571-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 227118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-123548571-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00664 (1002/150856) while in subpopulation AFR AF= 0.0226 (929/41044). AF 95% confidence interval is 0.0214. There are 15 homozygotes in gnomad4. There are 460 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRDN	NM_006073.4 link	c.274G>A	p.Val92Ile	missense_variant	Exon 3 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.274G>A	p.Val92Ile	missense_variant	Exon 3 of 41	1	NM_006073.4	ENSP00000333984.5		Q13061-1

Frequencies

GnomAD3 genomes

AF:

0.00661

AC:

997

AN:

150740

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0226

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00358

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:

0.000118

Gnomad OTH

AF:

0.00532

GnomAD3 exomes

AF:

0.00155

AC:

289

AN:

186128

Hom.:

AF XY:

0.00118

AC XY:

118

AN XY:

100070

show subpopulations

Gnomad AFR exome

AF:

0.0232

Gnomad AMR exome

AF:

0.000993

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000430

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000371

Gnomad OTH exome

AF:

0.00108

GnomAD4 exome

AF:

0.000633

AC:

889

AN:

1404656

Hom.:

Cov.:

AF XY:

0.000537

AC XY:

373

AN XY:

695136

show subpopulations

Gnomad4 AFR exome

AF:

0.0229

Gnomad4 AMR exome

AF:

0.00153

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000781

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000832

Gnomad4 OTH exome

AF:

0.00136

GnomAD4 genome

AF:

0.00664

AC:

1002

AN:

150856

Hom.:

Cov.:

AF XY:

0.00625

AC XY:

460

AN XY:

73580

show subpopulations

Gnomad4 AFR

AF:

0.0226

Gnomad4 AMR

AF:

0.00358

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00526

Alfa

AF:

0.00103

Hom.:

Bravo

AF:

0.00765

ESP6500AA

AF:

0.0229

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.00170

AC:

204

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Nov 29, 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. -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Val92Ile in exon 3 of TRDN: This variant is not expected to have clinical signif icance because it has been identified in 2.3% (84/3676) of African American chro mosomes from a broad population by the NHLBI Exome Sequencing Project (http://ev s.gs.washington.edu/EVS; dbSNP rs34808221). -

May 20, 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.274G>A (p.Val92Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 186128 control chromosomes, predominantly at a frequency of 0.023 within the African or African-American subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 15 fold of the estimated maximal expected allele frequency for a pathogenic variant in TRDN causing Catecholaminergic Polymorphic Ventricular Tachycardia phenotype (0.0016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.274G>A 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: 227118). Based on the evidence outlined above, the variant was classified as likely benign. -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

T;.;.;.

Eigen

Benign

0.051

Eigen_PC

Benign

0.14

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.75

T;T;T;T

MetaRNN

Benign

0.0039

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;L;.;L

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.37

N;.;N;N

REVEL

Benign

0.055

Sift

Benign

0.17

T;.;T;T

Sift4G

Benign

0.58

T;T;T;T

Polyphen

0.78

P;.;.;.

Vest4

0.086

MVP

0.17

ClinPred

0.0087

GERP RS

4.4

Varity_R

0.053

gMVP

0.13

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over