6-123366180-T-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_006073.4(TRDN):​c.1276A>C​(p.Thr426Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,612,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. T426A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: TRDN NM_006073.4 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14823833).
• BP6: Variant 6-123366180-T-G is Benign according to our data. Variant chr6-123366180-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 532313.

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>C	p.Thr426Pro	missense splice_region	Exon 20 of 41	NP_006064.2	Q13061-1
	TRDN	NM_001251987.2		c.1279A>C	p.Thr427Pro	missense splice_region	Exon 20 of 21	NP_001238916.1	A0A590UJV0
	TRDN	NM_001407315.1		c.1219A>C	p.Thr407Pro	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>C	p.Thr426Pro	missense splice_region	Exon 20 of 41	ENSP00000333984.5	Q13061-1
	TRDN	ENST00000962661.1		c.1279A>C	p.Thr427Pro	missense splice_region	Exon 20 of 41	ENSP00000632720.1
	TRDN	ENST00000962654.1		c.1276A>C	p.Thr426Pro	missense splice_region	Exon 20 of 41	ENSP00000632713.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000805 AC: 2 AN: 248566 AF XY: 0.00000742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000260 AC: 38 AN: 1460664 Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18 AN XY: 726624

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.00 AC: 0 AN: 86182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000306 AC: 34 AN: 1111214

Other (OTH) AF: 0.0000663 AC: 4 AN: 60338

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152206 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000579 Hom.: 0

Bravo AF: 0.0000529

EpiCase AF: 0.0000546

EpiControl AF: 0.0000594

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)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.096
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.0
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.056
Sift	Uncertain	0.020	D
Sift4G	Benign	0.29	T
Polyphen		0.88	P
Vest4		0.13
MVP		0.081
ClinPred		0.29	T
GERP RS		3.2
Varity_R		0.11
gMVP		0.0073
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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;