rs7771303

Variant names:

• chr6-123273341-T-C
• rs7771303
• NM_006073.4:c.1620A>G
• TRDN p.Ile540Met

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -14 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_ModerateBP6_Strong

The NM_006073.4(TRDN):c.1620A>G (p.Ile540Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00714 (AC=7,524) in the gnomAD database across 1,054,006 control chromosomes, including 238 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.071. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: 𝑓 0.017 (69 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (169 hom.)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.662
• Publications: 1 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: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• familial long QT syndrome

  Inheritance: AR Classification: STRONG Submitted by: G2P
• long QT syndrome

  Inheritance: AR Classification: STRONG Submitted by: ClinGen

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -14 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 2 star(s). ClinVar submissions strongly and reliably favor benignity (11/11 total B/LB).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.0710 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TRDN NM_006073.4	MANE Select	c.1620A>G p.Ile540Met	missense	Exon 28 of 41	Prot: NP_006064.2 UniProt:

TRDN NM_006073.4

MANE Select

HGVSc / HGVSpc.1620A>Gp.Ile540Met

Exon rankExon 28 of 41

missense

Prot: NP_006064.2UniProt: Q13061-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TRDN ENST00000334268.9	TSL:1MANE Select	c.1620A>G p.Ile540Met	missense	Exon 28 of 41	Prot: ENSP00000333984.5 UniProt:
	TRDN ENST00000962661.1		c.1623A>G p.Ile541Met	missense	Exon 28 of 41	Prot: ENSP00000632720.1 UniProt:
	TRDN ENST00000962654.1		c.1620A>G p.Ile540Met	missense	Exon 28 of 41	Prot: ENSP00000632713.1 UniProt:

TRDN ENST00000334268.9

TSL:1MANE Select

HGVSc / HGVSpc.1620A>Gp.Ile540Met

Exon rankExon 28 of 41

missense

Prot: ENSP00000333984.5UniProt: Q13061-1

TRDN ENST00000962661.1

HGVSc / HGVSpc.1623A>Gp.Ile541Met

Exon rankExon 28 of 41

missense

Prot: ENSP00000632720.1UniProt: A0ACI8VCI3

TRDN ENST00000962654.1

HGVSc / HGVSpc.1620A>Gp.Ile540Met

Exon rankExon 28 of 41

missense

Prot: ENSP00000632713.1UniProt: A0ACI8VA17

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0173	AC:2619	Hom:68	AN:151062	Cov:32
GnomAD2 exomes	AF: 0.0151	AC:1201	Hom:	AN:79470	Cov:
GnomAD4 exome	AF: 0.00543	AC:4906	Hom:169	AN:902826	Cov:13
GnomAD4 genome	AF: 0.0173	AC:2618	Hom:69	AN:151180	Cov:32
TOPMed (Bravo)	AF: 0.0162	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00885	AC:1048	Hom:18	AN:118420	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.0115	AC:27	Hom:0	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.0468	AC:	Hom:	AN:	Cov:
ESP6500 (Exome Variant Server)	AF: 0.0113	AC:91	Hom:	AN:8024	Cov:
GenomeAsia100K	AF: 0.0580	AC:202	Hom:	AN:3438	Cov:
Korea4K (4,157 Koreans)	AF: 0.0390	AC:284	Hom:	AN:7206	Cov:
Qatari Genome	AF: 0.0402	AC:7	Hom:	AN:174	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0178	AC:2161	Hom:20	AN:121611	Cov:
Turkish Variome	AF: 0.00841	AC:13	Hom:1	AN:1546	Cov:
UK10K	AF: 0.000793	AC:6	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.0406	AC:364	Hom:8	AN:8960	Cov:

Showing 16 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.0136	308	22706	0.00689	201	29192

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1 (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 5 (1)
-	-	1	not provided (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	1.5
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.087
DANN	Benign	0.84
DEOGEN2	Benign	0.085	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.012	N
FuncVEP CTI	Benign	0.014
GPN-Star LLR	N/A	-1.4
GPN-Star score	N/A	1.4
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.93	T
Mutation Taster	N/A	95/5	polymorphism (auto)
MutationAssessor	Benign	0.0	N
PhyloP100	Benign	-0.66
popEVE	Benign	-3.4
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.29	N
REVEL	Benign	0.026
Sift	Uncertain	0.025	D
Sift4G	Benign	0.19	T
Varity_R	N/A	0.057
VESM-3B	Benign	-3.8

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.020
SpliceAI score (max)	Benign	0.040	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs7771303;

hg19: chr6-123594486;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar