rs2873479

Variant names:

• chr6-123366143-A-C
• rs2873479
• NM_006073.4:c.1313T>G

Your query was ambiguous. Multiple possible variants found:

• chr6-123366143-A-C
• chr6-123366143-A-G
• chr6-123366143-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006073.4(TRDN):​c.1313T>G​(p.Ile438Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.913 in 1,611,814 control chromosomes in the GnomAD database, including 672,491 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 Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I438N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.93 (65176 hom., cov: 32)
  • Exomes 𝑓: 0.91 (607315 hom.)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 2.38
• Publications: 30 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.387485E-7).
• BP6: Variant 6-123366143-A-C is Benign according to our data. Variant chr6-123366143-A-C is described in ClinVar as Benign. ClinVar VariationId is 227110.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.943 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRDN	NM_006073.4	c.1313T>G	p.Ile438Ser	missense_variant	Exon 20 of 41	ENST00000334268.9	NP_006064.2
TRDN	NM_001251987.2	c.1316T>G	p.Ile439Ser	missense_variant	Exon 20 of 21		NP_001238916.1
TRDN	NM_001407315.1	c.1256T>G	p.Ile419Ser	missense_variant	Exon 19 of 20		NP_001394244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9	c.1313T>G	p.Ile438Ser	missense_variant	Exon 20 of 41	1	NM_006073.4	ENSP00000333984.5
TRDN	ENST00000662930.1	c.1316T>G	p.Ile439Ser	missense_variant	Exon 20 of 21			ENSP00000499585.1

Frequencies

GnomAD3 genomes AF: 0.925 AC: 140688 AN: 152080 Hom.: 65116 Cov.: 32

Gnomad AFR AF: 0.951

Gnomad AMI AF: 0.868

Gnomad AMR AF: 0.938

Gnomad ASJ AF: 0.905

Gnomad EAS AF: 0.920

Gnomad SAS AF: 0.940

Gnomad FIN AF: 0.922

Gnomad MID AF: 0.930

Gnomad NFE AF: 0.908

Gnomad OTH AF: 0.932

GnomAD2 exomes AF: 0.925 AC: 229675 AN: 248196 AF XY: 0.924

Gnomad AFR exome AF: 0.952

Gnomad AMR exome AF: 0.964

Gnomad ASJ exome AF: 0.908

Gnomad EAS exome AF: 0.915

Gnomad FIN exome AF: 0.928

Gnomad NFE exome AF: 0.909

Gnomad OTH exome AF: 0.927

GnomAD4 exome AF: 0.912 AC: 1331268 AN: 1459616 Hom.: 607315 Cov.: 37 AF XY: 0.912 AC XY: 662484 AN XY: 726108

African (AFR) AF: 0.953 AC: 31868 AN: 33446

American (AMR) AF: 0.965 AC: 43051 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.909 AC: 23719 AN: 26088

East Asian (EAS) AF: 0.925 AC: 36621 AN: 39588

South Asian (SAS) AF: 0.937 AC: 80659 AN: 86074

European-Finnish (FIN) AF: 0.925 AC: 49311 AN: 53290

Middle Eastern (MID) AF: 0.934 AC: 5374 AN: 5756

European-Non Finnish (NFE) AF: 0.906 AC: 1005539 AN: 1110452

Other (OTH) AF: 0.914 AC: 55126 AN: 60290

GnomAD4 genome AF: 0.925 AC: 140809 AN: 152198 Hom.: 65176 Cov.: 32 AF XY: 0.925 AC XY: 68844 AN XY: 74398

African (AFR) AF: 0.951 AC: 39467 AN: 41522

American (AMR) AF: 0.938 AC: 14347 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.905 AC: 3139 AN: 3470

East Asian (EAS) AF: 0.920 AC: 4745 AN: 5158

South Asian (SAS) AF: 0.940 AC: 4536 AN: 4824

European-Finnish (FIN) AF: 0.922 AC: 9777 AN: 10600

Middle Eastern (MID) AF: 0.939 AC: 276 AN: 294

European-Non Finnish (NFE) AF: 0.908 AC: 61756 AN: 68006

Other (OTH) AF: 0.933 AC: 1974 AN: 2116

Alfa AF: 0.915 Hom.: 173975

Bravo AF: 0.931

TwinsUK AF: 0.908 AC: 3366

ALSPAC AF: 0.899 AC: 3463

ESP6500AA AF: 0.948 AC: 3431

ESP6500EA AF: 0.916 AC: 7466

ExAC AF: 0.924 AC: 111543

EpiCase AF: 0.908

EpiControl AF: 0.907

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

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

Ile438Ser in exon 20 of TRDN: This variant is not expected to have clinical sign ificance because it has been identified in 8.4% (688/8154) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs2873479). -

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

- -

Sep 21, 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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Catecholaminergic polymorphic ventricular tachycardia 5 Benign:2

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	17
DANN	Benign	0.69
DEOGEN2	Benign	0.064	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.23	T
MetaRNN	Benign	8.4e-7	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.4
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.52	N
REVEL	Benign	0.062
Sift	Benign	0.41	T
Sift4G	Benign	0.79	T
Polyphen		0.0	B
Vest4		0.015
ClinPred		0.0039	T
GERP RS		4.7
Varity_R		0.046
gMVP		0.0054
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2873479; hg19: chr6-123687288; COSMIC: COSV107392655;