NM_006073.4:c.403G>A

Variant names:

• chr6-123547361-C-T
• rs192289289
• NM_006073.4:c.403G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006073.4(TRDN):​c.403G>A​(p.Glu135Lys) variant causes a missense change. The variant allele was found at a frequency of 0.01 in 1,458,352 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts 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. E135E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0085 (6 hom., cov: 32)
  • Exomes 𝑓: 0.010 (82 hom.)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.76
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008121401).
• BP6: Variant 6-123547361-C-T is Benign according to our data. Variant chr6-123547361-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00849 (1289/151898) while in subpopulation NFE AF = 0.0148 (1005/67906). AF 95% confidence interval is 0.014. There are 6 homozygotes in GnomAd4. There are 580 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

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.403G>A	p.Glu135Lys	missense	Exon 4 of 41	NP_006064.2	Q13061-1
	TRDN	NM_001251987.2		c.403G>A	p.Glu135Lys	missense	Exon 4 of 21	NP_001238916.1	A0A590UJV0
	TRDN	NM_001407315.1		c.403G>A	p.Glu135Lys	missense	Exon 4 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.403G>A	p.Glu135Lys	missense	Exon 4 of 41	ENSP00000333984.5	Q13061-1
	TRDN	ENST00000628709.2	TSL:1	c.403G>A	p.Glu135Lys	missense	Exon 4 of 9	ENSP00000486095.1	Q13061-2
	TRDN	ENST00000546248.6	TSL:1	c.403G>A	p.Glu135Lys	missense	Exon 4 of 8	ENSP00000439281.2	H9ME53

Frequencies

GnomAD3 genomes AF: 0.00849 AC: 1289 AN: 151780 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00285

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00440

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00674

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.00719

GnomAD2 exomes AF: 0.00692 AC: 782 AN: 113040 AF XY: 0.00690

Gnomad AFR exome AF: 0.00272

Gnomad AMR exome AF: 0.00160

Gnomad ASJ exome AF: 0.000435

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00790

Gnomad NFE exome AF: 0.0119

Gnomad OTH exome AF: 0.00695

GnomAD4 exome AF: 0.0102 AC: 13360 AN: 1306454 Hom.: 82 Cov.: 24 AF XY: 0.00992 AC XY: 6382 AN XY: 643240

African (AFR) AF: 0.00165 AC: 45 AN: 27244

American (AMR) AF: 0.00163 AC: 38 AN: 23350

Ashkenazi Jewish (ASJ) AF: 0.000388 AC: 9 AN: 23192

East Asian (EAS) AF: 0.00 AC: 0 AN: 32766

South Asian (SAS) AF: 0.00155 AC: 97 AN: 62666

European-Finnish (FIN) AF: 0.00818 AC: 394 AN: 48152

Middle Eastern (MID) AF: 0.00185 AC: 10 AN: 5416

European-Non Finnish (NFE) AF: 0.0120 AC: 12377 AN: 1029466

Other (OTH) AF: 0.00720 AC: 390 AN: 54202

GnomAD4 genome AF: 0.00849 AC: 1289 AN: 151898 Hom.: 6 Cov.: 32 AF XY: 0.00781 AC XY: 580 AN XY: 74224

African (AFR) AF: 0.00285 AC: 118 AN: 41460

American (AMR) AF: 0.00440 AC: 67 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4808

European-Finnish (FIN) AF: 0.00674 AC: 71 AN: 10534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0148 AC: 1005 AN: 67906

Other (OTH) AF: 0.00712 AC: 15 AN: 2108

Alfa AF: 0.0110 Hom.: 35

Bravo AF: 0.00763

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.0163 AC: 63

ESP6500AA AF: 0.00294 AC: 10

ESP6500EA AF: 0.00991 AC: 76

ExAC AF: 0.00360 AC: 373

Asia WGS AF: 0.000584 AC: 2 AN: 3440

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1 (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 5 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0081	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.8
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.25
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.32	T
Polyphen		1.0	D
Vest4		0.29
MVP		0.68
ClinPred		0.0062	T
GERP RS		5.7
Varity_R		0.22
gMVP		0.023
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs192289289; hg19: chr6-123868506; COSMIC: COSV99043837;