chr6-123366180-T-C

Variant names:

• chr6-123366180-T-C
• rs1040336692
• NM_006073.4:c.1276A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_006073.4(TRDN):​c.1276A>G​(p.Thr426Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T426P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TRDN NM_006073.4 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.02
• Publications: 0 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

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05627492).
• BP6: Variant 6-123366180-T-C is Benign according to our data. Variant chr6-123366180-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1507019.

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.1276A>G	p.Thr426Ala	missense splice_region	Exon 20 of 41	NP_006064.2	Q13061-1
	TRDN	NM_001251987.2		c.1279A>G	p.Thr427Ala	missense splice_region	Exon 20 of 21	NP_001238916.1	A0A590UJV0
	TRDN	NM_001407315.1		c.1219A>G	p.Thr407Ala	missense splice_region	Exon 19 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.1276A>G	p.Thr426Ala	missense splice_region	Exon 20 of 41	ENSP00000333984.5	Q13061-1
	TRDN	ENST00000962661.1		c.1279A>G	p.Thr427Ala	missense splice_region	Exon 20 of 41	ENSP00000632720.1
	TRDN	ENST00000962654.1		c.1276A>G	p.Thr426Ala	missense splice_region	Exon 20 of 41	ENSP00000632713.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	16
DANN	Benign	0.85
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.0
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.011
Sift	Benign	0.55	T
Sift4G	Benign	0.76	T
Polyphen		0.0010	B
Vest4		0.054
MutPred		0.28		Loss of phosphorylation at T426 (P = 0.0245)
MVP		0.040
ClinPred		0.072	T
GERP RS		3.2
Varity_R		0.033
gMVP		0.0083
Mutation Taster		=94/6	polymorphism

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: rs1040336692; hg19: chr6-123687325;