rs7771303

Variant names:

• chr6-123273341-T-C
• rs7771303
• NM_006073.4:c.1620A>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.1620A>G​(p.Ile540Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00714 in 1,054,006 control chromosomes in the GnomAD database, including 238 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 Likely benign (★★).

• 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:10
• Conservation: PhyloP100: -0.662
• Publications: 8 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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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=0.0018236339).
• BP6: Variant 6-123273341-T-C is Benign according to our data. Variant chr6-123273341-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.071 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

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

Sel.	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
	TRDN	ENST00000962654.1		c.1620A>G	p.Ile540Met	missense	Exon 28 of 41	ENSP00000632713.1

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2619 AN: 151062 Hom.: 68 Cov.: 32

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

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.: 13 AF XY: 0.00749 AC XY: 3379 AN XY: 451238

African (AFR) AF: 0.0304 AC: 524 AN: 17228

American (AMR) AF: 0.00272 AC: 30 AN: 11014

Ashkenazi Jewish (ASJ) AF: 0.000464 AC: 8 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: 29 AN: 4120

European-Non Finnish (NFE) AF: 0.000402 AC: 286 AN: 712074

Other (OTH) AF: 0.00635 AC: 239 AN: 37634

GnomAD4 genome AF: 0.0173 AC: 2618 AN: 151180 Hom.: 69 Cov.: 32 AF XY: 0.0190 AC XY: 1405 AN XY: 73816

African (AFR) AF: 0.0442 AC: 1833 AN: 41496

American (AMR) AF: 0.00556 AC: 84 AN: 15110

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 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: 72 AN: 10412

Middle Eastern (MID) AF: 0.0105 AC: 3 AN: 286

European-Non Finnish (NFE) AF: 0.000944 AC: 64 AN: 67772

Other (OTH) AF: 0.0133 AC: 28 AN: 2104

Alfa AF: 0.00782 Hom.: 12

Bravo AF: 0.0162

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.0348 AC: 86

ESP6500EA AF: 0.000901 AC: 5

ExAC AF: 0.0228 AC: 690

Asia WGS AF: 0.0580 AC: 202 AN: 3438

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1 (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 5 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
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
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.66
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.29	N
REVEL	Benign	0.026
Sift	Uncertain	0.025	D
Sift4G	Benign	0.19	T
Polyphen		0.0040	B
Vest4		0.045
ClinPred		0.0041	T
GERP RS		-3.8
Varity_R		0.057
gMVP		0.0031
Mutation Taster		=95/5	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: rs7771303; hg19: chr6-123594486;