rs28494009

Variant names:

• chr6-123377874-A-C
• rs28494009
• NM_006073.4:c.1211T>G

Your query was ambiguous. Multiple possible variants found:

• chr6-123377874-A-C
• chr6-123377874-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.1211T>G​(p.Val404Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 1,533,254 control chromosomes in the GnomAD database, including 18,325 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2175 hom., cov: 32)
  • Exomes 𝑓: 0.15 (16150 hom.)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0250
• Publications: 19 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=0.0028282404).
• BP6: Variant 6-123377874-A-C is Benign according to our data. Variant chr6-123377874-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.21 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRDN	NM_006073.4	c.1211T>G	p.Val404Gly	missense_variant	Exon 17 of 41	ENST00000334268.9	NP_006064.2
TRDN	NM_001251987.2	c.1214T>G	p.Val405Gly	missense_variant	Exon 17 of 21		NP_001238916.1
TRDN	NM_001407315.1	c.1154T>G	p.Val385Gly	missense_variant	Exon 16 of 20		NP_001394244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9	c.1211T>G	p.Val404Gly	missense_variant	Exon 17 of 41	1	NM_006073.4	ENSP00000333984.5
TRDN	ENST00000662930.1	c.1214T>G	p.Val405Gly	missense_variant	Exon 17 of 21			ENSP00000499585.1

Frequencies

GnomAD3 genomes AF: 0.164 AC: 24966 AN: 152002 Hom.: 2175 Cov.: 32

Gnomad AFR AF: 0.201

Gnomad AMI AF: 0.238

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.0806

Gnomad EAS AF: 0.0785

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.134

GnomAD2 exomes AF: 0.152 AC: 28782 AN: 188752 AF XY: 0.158

Gnomad AFR exome AF: 0.204

Gnomad AMR exome AF: 0.0829

Gnomad ASJ exome AF: 0.0821

Gnomad EAS exome AF: 0.0834

Gnomad FIN exome AF: 0.197

Gnomad NFE exome AF: 0.152

Gnomad OTH exome AF: 0.131

GnomAD4 exome AF: 0.148 AC: 203831 AN: 1381138 Hom.: 16150 Cov.: 28 AF XY: 0.151 AC XY: 103345 AN XY: 686038

African (AFR) AF: 0.195 AC: 6106 AN: 31260

American (AMR) AF: 0.0839 AC: 3222 AN: 38398

Ashkenazi Jewish (ASJ) AF: 0.0820 AC: 2063 AN: 25170

East Asian (EAS) AF: 0.0651 AC: 2471 AN: 37936

South Asian (SAS) AF: 0.228 AC: 18322 AN: 80252

European-Finnish (FIN) AF: 0.197 AC: 10006 AN: 50770

Middle Eastern (MID) AF: 0.0930 AC: 453 AN: 4872

European-Non Finnish (NFE) AF: 0.145 AC: 153170 AN: 1054996

Other (OTH) AF: 0.139 AC: 8018 AN: 57484

GnomAD4 genome AF: 0.164 AC: 24961 AN: 152116 Hom.: 2175 Cov.: 32 AF XY: 0.165 AC XY: 12257 AN XY: 74350

African (AFR) AF: 0.201 AC: 8346 AN: 41514

American (AMR) AF: 0.109 AC: 1671 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0806 AC: 280 AN: 3472

East Asian (EAS) AF: 0.0779 AC: 404 AN: 5184

South Asian (SAS) AF: 0.221 AC: 1066 AN: 4824

European-Finnish (FIN) AF: 0.198 AC: 2096 AN: 10566

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.156 AC: 10580 AN: 67974

Other (OTH) AF: 0.133 AC: 281 AN: 2112

Alfa AF: 0.150 Hom.: 3633

Bravo AF: 0.156

TwinsUK AF: 0.155 AC: 573

ALSPAC AF: 0.166 AC: 640

ESP6500AA AF: 0.189 AC: 671

ESP6500EA AF: 0.145 AC: 1178

ExAC AF: 0.137 AC: 15894

Asia WGS AF: 0.155 AC: 541 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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

- -

Apr 10, 2023

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 26, 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

Val404Gly in exon 17 of TRDN: This variant is not expected to have clinical sign ificance because it has been identified in 18.9% (671/3550) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs28494009). -

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 23, 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	0.11
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.025
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.024
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.37	T
Polyphen		0.047	B
Vest4		0.080
ClinPred		0.018	T
GERP RS		-0.35
Varity_R		0.13
gMVP		0.016
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs28494009; hg19: chr6-123699019; COSMIC: COSV62116563;