rs545032318

Variant names:

• chr6-123516189-C-A
• rs545032318
• NM_006073.4:c.502G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-123516189-C-A
• chr6-123516189-C-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_006073.4(TRDN):​c.502G>T​(p.Glu168*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000203 in 1,332,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: TRDN NM_006073.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.03
• 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: 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: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 6-123516189-C-A is Pathogenic according to our data. Variant chr6-123516189-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 838068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.502G>T	p.Glu168*	stop_gained	Exon 6 of 41	NP_006064.2
	TRDN	NM_001251987.2		c.502G>T	p.Glu168*	stop_gained	Exon 6 of 21	NP_001238916.1
	TRDN	NM_001407315.1		c.502G>T	p.Glu168*	stop_gained	Exon 6 of 20	NP_001394244.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRDN	ENST00000334268.9	TSL:1 MANE Select	c.502G>T	p.Glu168*	stop_gained	Exon 6 of 41	ENSP00000333984.5
	TRDN	ENST00000628709.2	TSL:1	c.502G>T	p.Glu168*	stop_gained	Exon 6 of 9	ENSP00000486095.1
	TRDN	ENST00000546248.6	TSL:1	c.502G>T	p.Glu168*	stop_gained	Exon 6 of 8	ENSP00000439281.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000203 AC: 27 AN: 1332006 Hom.: 0 Cov.: 29 AF XY: 0.0000184 AC XY: 12 AN XY: 652602

African (AFR) AF: 0.00 AC: 0 AN: 29710

American (AMR) AF: 0.00 AC: 0 AN: 30912

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23188

East Asian (EAS) AF: 0.00 AC: 0 AN: 32738

South Asian (SAS) AF: 0.00 AC: 0 AN: 75010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43802

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5262

European-Non Finnish (NFE) AF: 0.0000260 AC: 27 AN: 1037082

Other (OTH) AF: 0.00 AC: 0 AN: 54302

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Catecholaminergic polymorphic ventricular tachycardia 1 (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Catecholaminergic polymorphic ventricular tachycardia 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Pathogenic	0.89
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Benign	0.74	D
PhyloP100		3.0
Vest4		0.68
ClinPred		1.0	D
GERP RS		3.8
PromoterAI		-0.0086	Neutral
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs545032318; hg19: chr6-123837334; COSMIC: COSV62121091;