6-123548462-G-C

Variant names:

• chr6-123548462-G-C
• rs9490809
• NM_006073.4:c.383C>G

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.383C>G​(p.Thr128Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.508 in 1,556,642 control chromosomes in the GnomAD database, including 207,684 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T128T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.50 (19905 hom., cov: 30)
  • Exomes 𝑓: 0.51 (187779 hom.)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.0810
• Publications: 27 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

ENSG00000285691 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=2.3423745E-5).
• BP6: Variant 6-123548462-G-C is Benign according to our data. Variant chr6-123548462-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.533 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006073.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRDN	NM_006073.4	MANE Select	c.383C>G	p.Thr128Ser	missense	Exon 3 of 41	NP_006064.2
	TRDN	NM_001251987.2		c.383C>G	p.Thr128Ser	missense	Exon 3 of 21	NP_001238916.1
	TRDN	NM_001407315.1		c.383C>G	p.Thr128Ser	missense	Exon 3 of 20	NP_001394244.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRDN	ENST00000334268.9	TSL:1 MANE Select	c.383C>G	p.Thr128Ser	missense	Exon 3 of 41	ENSP00000333984.5
	TRDN	ENST00000628709.2	TSL:1	c.383C>G	p.Thr128Ser	missense	Exon 3 of 9	ENSP00000486095.1
	TRDN	ENST00000546248.6	TSL:1	c.383C>G	p.Thr128Ser	missense	Exon 3 of 8	ENSP00000439281.2

Frequencies

GnomAD3 genomes AF: 0.503 AC: 76085 AN: 151308 Hom.: 19898 Cov.: 30

Gnomad AFR AF: 0.539

Gnomad AMI AF: 0.453

Gnomad AMR AF: 0.387

Gnomad ASJ AF: 0.580

Gnomad EAS AF: 0.0824

Gnomad SAS AF: 0.392

Gnomad FIN AF: 0.583

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.531

Gnomad OTH AF: 0.507

GnomAD2 exomes AF: 0.442 AC: 86427 AN: 195600 AF XY: 0.448

Gnomad AFR exome AF: 0.531

Gnomad AMR exome AF: 0.250

Gnomad ASJ exome AF: 0.578

Gnomad EAS exome AF: 0.0792

Gnomad FIN exome AF: 0.571

Gnomad NFE exome AF: 0.517

Gnomad OTH exome AF: 0.481

GnomAD4 exome AF: 0.509 AC: 715045 AN: 1405216 Hom.: 187779 Cov.: 33 AF XY: 0.507 AC XY: 352821 AN XY: 696268

African (AFR) AF: 0.543 AC: 16908 AN: 31164

American (AMR) AF: 0.278 AC: 10005 AN: 36012

Ashkenazi Jewish (ASJ) AF: 0.583 AC: 14152 AN: 24268

East Asian (EAS) AF: 0.109 AC: 4184 AN: 38530

South Asian (SAS) AF: 0.397 AC: 30240 AN: 76146

European-Finnish (FIN) AF: 0.573 AC: 29209 AN: 50958

Middle Eastern (MID) AF: 0.494 AC: 2756 AN: 5574

European-Non Finnish (NFE) AF: 0.534 AC: 578838 AN: 1084692

Other (OTH) AF: 0.497 AC: 28753 AN: 57872

GnomAD4 genome AF: 0.503 AC: 76121 AN: 151426 Hom.: 19905 Cov.: 30 AF XY: 0.497 AC XY: 36810 AN XY: 73990

African (AFR) AF: 0.539 AC: 22246 AN: 41290

American (AMR) AF: 0.386 AC: 5861 AN: 15176

Ashkenazi Jewish (ASJ) AF: 0.580 AC: 2007 AN: 3458

East Asian (EAS) AF: 0.0820 AC: 423 AN: 5156

South Asian (SAS) AF: 0.393 AC: 1889 AN: 4812

European-Finnish (FIN) AF: 0.583 AC: 6137 AN: 10520

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.531 AC: 35939 AN: 67716

Other (OTH) AF: 0.507 AC: 1063 AN: 2096

Alfa AF: 0.507 Hom.: 14156

Bravo AF: 0.487

TwinsUK AF: 0.537 AC: 1990

ALSPAC AF: 0.529 AC: 2040

ESP6500AA AF: 0.549 AC: 2066

ESP6500EA AF: 0.537 AC: 4418

ExAC AF: 0.422 AC: 50234

Asia WGS AF: 0.267 AC: 931 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 22, 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

Apr 04, 2023

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

Significance: Likely 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

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

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Thr128Ser in exon 3 of TRDN: This variant is not expected to have clinical signi ficance because it has been identified in 46.3% (3802/8220) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs9490809).

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.98
DANN	Benign	0.24
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.000023	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	M
PhyloP100		-0.081
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.043
Sift	Benign	0.43	T
Sift4G	Benign	0.33	T
Polyphen		0.058	B
Vest4		0.031
MutPred		0.32		Gain of relative solvent accessibility (P = 0.09)
ClinPred		0.0053	T
GERP RS		2.0
Varity_R		0.034
gMVP		0.011
Mutation Taster		=64/36	polymorphism

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: rs9490809; hg19: chr6-123869607; COSMIC: COSV107392756;