rs7771303

Variant names:

Variant summary

Our verdict is 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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.662

Publications

8 publications found

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 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

TRDN links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_006073.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

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

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

BP6

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).

BA1

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	NP_006064.2	Q13061-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRDN	ENST00000334268.9	TSL:1 MANE Select	c.1620A>G	p.Ile540Met	missense	Exon 28 of 41	ENSP00000333984.5	Q13061-1
TRDN	ENST00000962661.1		c.1623A>G	p.Ile541Met	missense	Exon 28 of 41	ENSP00000632720.1	A0ACI8VCI3
TRDN	ENST00000962654.1		c.1620A>G	p.Ile540Met	missense	Exon 28 of 41	ENSP00000632713.1	A0ACI8VA17

Frequencies

GnomAD3 genomes

AF:

0.0173

AC:

2619

AN:

151062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0443

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00557

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.0339

Gnomad SAS

AF:

0.0777

Gnomad FIN

AF:

0.00692

Gnomad MID

AF:

0.0130

Gnomad NFE

AF:

0.000944

Gnomad OTH

AF:

0.0135

GnomAD2 exomes

AF:

0.0151

AC:

1201

AN:

79470

AF XY:

0.0185

show subpopulations

Gnomad AFR exome

AF:

0.0447

Gnomad AMR exome

AF:

0.00340

Gnomad ASJ exome

AF:

0.000200

Gnomad EAS exome

AF:

0.0412

Gnomad FIN exome

AF:

0.00591

Gnomad NFE exome

AF:

0.000703

Gnomad OTH exome

AF:

0.00549

GnomAD4 exome

AF:

0.00543

AC:

4906

AN:

902826

Hom.:

169

Cov.:

AF XY:

0.00749

AC XY:

3379

AN XY:

451238

show subpopulations

African (AFR)

AF:

0.0304

AC:

524

AN:

17228

American (AMR)

AF:

0.00272

AC:

AN:

11014

Ashkenazi Jewish (ASJ)

AF:

0.000464

AC:

AN:

17236

East Asian (EAS)

AF:

0.0155

AC:

252

AN:

16290

South Asian (SAS)

AF:

0.0618

AC:

3374

AN:

54612

European-Finnish (FIN)

AF:

0.00503

AC:

164

AN:

32618

Middle Eastern (MID)

AF:

0.00704

AC:

AN:

4120

European-Non Finnish (NFE)

AF:

0.000402

AC:

286

AN:

712074

Other (OTH)

AF:

0.00635

AC:

239

AN:

37634

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

171

343

514

686

857

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0173

AC:

2618

AN:

151180

Hom.:

Cov.:

AF XY:

0.0190

AC XY:

1405

AN XY:

73816

show subpopulations

African (AFR)

AF:

0.0442

AC:

1833

AN:

41496

American (AMR)

AF:

0.00556

AC:

AN:

15110

Ashkenazi Jewish (ASJ)

AF:

0.000577

AC:

AN:

3464

East Asian (EAS)

AF:

0.0339

AC:

167

AN:

4922

South Asian (SAS)

AF:

0.0776

AC:

365

AN:

4704

European-Finnish (FIN)

AF:

0.00692

AC:

AN:

10412

Middle Eastern (MID)

AF:

0.0105

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.000944

AC:

AN:

67772

Other (OTH)

AF:

0.0133

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

116

233

349

466

582

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

TOPMed (Bravo)

AF:

0.0162

ALFA (dbGaP/dbSNP Allele Frequency Aggregator)

AF:

0.00885

AC:

1048

AN:

118420

Hom.:

Local populations

ABraOM SABE-WGS-1171

AF:

0.0115

AC:

AN:

2342

Hom.:

ChinaMAP Phase 1

AF:

0.0468

ESP6500 (Exome Variant Server)

AF:

0.0113

AC:

AN:

8024

show subpopulations

European American

AF:

0.000901

AC:

AN:

5552

African American

AF:

0.0348

AC:

AN:

2472

GenomeAsia100K

AF:

0.0580

AC:

202

AN:

3438

show subpopulations

Oceania

AF:

0.00

AC:

AN:

148

Hom.:

North-East Asia

AF:

0.0314

AC:

AN:

700

Hom.:

South-East Asia

AF:

0.0434

AC:

AN:

692

Hom.:

South Asia

AF:

0.0915

AC:

129

AN:

1410

Hom.:

Africa

AF:

0.101

AC:

AN:

208

Hom.:

America

AF:

0.00

AC:

AN:

Hom.:

West Eurasia

AF:

0.00

AC:

AN:

228

Hom.:

Korea4K (4,157 Koreans)

AF:

0.0390

AC:

284

AN:

7206

Qatari Genome

AF:

0.0402

AC:

AN:

174

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.0178

AC:

2161

AN:

121611

Hom.:

Turkish Variome

AF:

0.00841

AC:

AN:

1546

Hom.:

UK10K

AF:

0.000793

AC:

AN:

7562

show subpopulations

TwinsUK

AF:

0.000560

AC:

AN:

3574

ALSPAC

AF:

0.00104

AC:

AN:

3854

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.0406

AC:

364

AN:

8960

Hom.:

Case/control cohorts

Cohort

Cases

Controls

SCHEMA

(Schizophrenia)

308 / 22706AF: 0.0135647

201 / 29192AF: 0.00688545

Allele 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

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

Cardiovascular phenotype (1)

Catecholaminergic polymorphic ventricular tachycardia 1 (1)

Catecholaminergic polymorphic ventricular tachycardia 5 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.087

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.085

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.42

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.0

PhyloP100

-0.66

PrimateAI

Benign

0.45

PROVEAN

Benign

0.29

REVEL

Benign

0.026

Sift

Uncertain

0.025

Sift4G

Benign

0.19

Varity_R

0.057

popEVE

Benign

-3.4

(source)

VESM-3B

Benign

-3.8

(source)

FuncVEP CTI

Benign

0.014

(source)

AlphaGenome AVI

Benign

1.5

(source)

GPN-Star LLR

-1.4

(source)

GPN-Star score

1.4

(source)

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Pangolin (max)

Benign

0.020

(source)

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.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

Case/control cohorts

ClinVar

Computational scores

Splicing

Publications

Other links and lift over