rs181287533

Variant names:

• chr6-123548606-G-A
• rs181287533
• NM_006073.4:c.239C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-123548606-G-A
• chr6-123548606-G-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_006073.4(TRDN):​c.239C>T​(p.Ser80Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000585 in 1,401,120 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000047 (1 hom.)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 5.76
• 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: 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

ENSG00000285691 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010376781).
• BP6: Variant 6-123548606-G-A is Benign according to our data. Variant chr6-123548606-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 449704.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00016 (23/143748) while in subpopulation AMR AF = 0.00139 (20/14366). AF 95% confidence interval is 0.000922. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

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.239C>T	p.Ser80Phe	missense	Exon 3 of 41	NP_006064.2	Q13061-1
	TRDN	NM_001251987.2		c.239C>T	p.Ser80Phe	missense	Exon 3 of 21	NP_001238916.1	A0A590UJV0
	TRDN	NM_001407315.1		c.239C>T	p.Ser80Phe	missense	Exon 3 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.239C>T	p.Ser80Phe	missense	Exon 3 of 41	ENSP00000333984.5	Q13061-1
	TRDN	ENST00000628709.2	TSL:1	c.239C>T	p.Ser80Phe	missense	Exon 3 of 9	ENSP00000486095.1	Q13061-2
	TRDN	ENST00000546248.6	TSL:1	c.239C>T	p.Ser80Phe	missense	Exon 3 of 8	ENSP00000439281.2	H9ME53

Frequencies

GnomAD3 genomes AF: 0.000160 AC: 23 AN: 143642 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000535

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00139

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: 0.00

Gnomad OTH AF: 0.000517

GnomAD2 exomes AF: 0.000404 AC: 35 AN: 86694 AF XY: 0.000253

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00753

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000541

GnomAD4 exome AF: 0.0000469 AC: 59 AN: 1257372 Hom.: 1 Cov.: 35 AF XY: 0.0000357 AC XY: 22 AN XY: 615930

African (AFR) AF: 0.00 AC: 0 AN: 26134

American (AMR) AF: 0.00350 AC: 55 AN: 15718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20412

East Asian (EAS) AF: 0.00 AC: 0 AN: 31546

South Asian (SAS) AF: 0.00 AC: 0 AN: 51000

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5092

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1011678

Other (OTH) AF: 0.0000782 AC: 4 AN: 51168

GnomAD4 genome AF: 0.000160 AC: 23 AN: 143748 Hom.: 0 Cov.: 31 AF XY: 0.000215 AC XY: 15 AN XY: 69738

African (AFR) AF: 0.0000534 AC: 2 AN: 37488

American (AMR) AF: 0.00139 AC: 20 AN: 14366

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3398

East Asian (EAS) AF: 0.00 AC: 0 AN: 5054

South Asian (SAS) AF: 0.00 AC: 0 AN: 4578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66314

Other (OTH) AF: 0.000511 AC: 1 AN: 1956

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000359

ExAC AF: 0.000520 AC: 58

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	-	Catecholaminergic polymorphic ventricular tachycardia 5 (1)
-	1	-	not specified (1)
-	-	1	TRDN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Benign	0.0094	T
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.8
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.71
MVP		0.77
ClinPred		0.23	T
GERP RS		5.3
Varity_R		0.55
gMVP		0.42
Mutation Taster		=93/7	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: rs181287533; hg19: chr6-123869751;