rs6569336

Variant names:

• chr6-123337631-G-T
• rs6569336
• NM_006073.4:c.1408C>A

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.1408C>A​(p.Leu470Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,422,180 control chromosomes in the GnomAD database, including 3,068 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L470L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.085 (1786 hom., cov: 32)
  • Exomes 𝑓: 0.010 (1282 hom.)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0770
• Publications: 9 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: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• 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

LOC105377984 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048668683).
• BP6: Variant 6-123337631-G-T is Benign according to our data. Variant chr6-123337631-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.284 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.1408C>A	p.Leu470Met	missense	Exon 22 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.1408C>A	p.Leu470Met	missense	Exon 22 of 41	ENSP00000333984.5	Q13061-1
	TRDN	ENST00000962661.1		c.1411C>A	p.Leu471Met	missense	Exon 22 of 41	ENSP00000632720.1
	TRDN	ENST00000962654.1		c.1408C>A	p.Leu470Met	missense	Exon 22 of 41	ENSP00000632713.1

Frequencies

GnomAD3 genomes AF: 0.0851 AC: 12923 AN: 151898 Hom.: 1783 Cov.: 32

Gnomad AFR AF: 0.289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0303

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.0639

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00118

Gnomad OTH AF: 0.0628

GnomAD2 exomes AF: 0.0247 AC: 3225 AN: 130400 AF XY: 0.0240

Gnomad AFR exome AF: 0.275

Gnomad AMR exome AF: 0.0128

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00121

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00145

Gnomad OTH exome AF: 0.0121

GnomAD4 exome AF: 0.0105 AC: 13318 AN: 1270164 Hom.: 1282 Cov.: 20 AF XY: 0.0112 AC XY: 7009 AN XY: 628308

African (AFR) AF: 0.277 AC: 7291 AN: 26360

American (AMR) AF: 0.0154 AC: 411 AN: 26722

Ashkenazi Jewish (ASJ) AF: 0.000216 AC: 5 AN: 23126

East Asian (EAS) AF: 0.000686 AC: 22 AN: 32058

South Asian (SAS) AF: 0.0577 AC: 3833 AN: 66412

European-Finnish (FIN) AF: 0.0000215 AC: 1 AN: 46568

Middle Eastern (MID) AF: 0.0149 AC: 71 AN: 4772

European-Non Finnish (NFE) AF: 0.000556 AC: 551 AN: 991756

Other (OTH) AF: 0.0216 AC: 1133 AN: 52390

GnomAD4 genome AF: 0.0852 AC: 12946 AN: 152016 Hom.: 1786 Cov.: 32 AF XY: 0.0821 AC XY: 6103 AN XY: 74326

African (AFR) AF: 0.288 AC: 11949 AN: 41438

American (AMR) AF: 0.0302 AC: 461 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5174

South Asian (SAS) AF: 0.0639 AC: 308 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00118 AC: 80 AN: 67974

Other (OTH) AF: 0.0621 AC: 131 AN: 2108

Alfa AF: 0.0326 Hom.: 1107

Bravo AF: 0.0954

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.252 AC: 572

ESP6500EA AF: 0.000800 AC: 4

ExAC AF: 0.0460 AC: 1142

Asia WGS AF: 0.0480 AC: 167 AN: 3470

ClinVar

ClinVar submissions

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.077
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.021
Sift	Uncertain	0.019	D
Sift4G	Benign	0.15	T
Polyphen		0.61	P
Vest4		0.064
ClinPred		0.0031	T
GERP RS		0.78
Varity_R		0.082
gMVP		0.0093
Mutation Taster		=98/2	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: rs6569336; hg19: chr6-123658776;