NM_006073.4:c.1055C>T

Variant names:

• chr6-123393674-G-A
• rs754708708
• NM_006073.4:c.1055C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_006073.4(TRDN):​c.1055C>T​(p.Pro352Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000053 in 1,604,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P352Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.63
• 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-AS1 (HGNC:40592): (TRDN antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04761064).

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.1055C>T	p.Pro352Leu	missense	Exon 13 of 41	NP_006064.2	Q13061-1
	TRDN	NM_001251987.2		c.1058C>T	p.Pro353Leu	missense	Exon 13 of 21	NP_001238916.1	A0A590UJV0
	TRDN	NM_001407315.1		c.998C>T	p.Pro333Leu	missense	Exon 12 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.1055C>T	p.Pro352Leu	missense	Exon 13 of 41	ENSP00000333984.5	Q13061-1
	TRDN	ENST00000962661.1		c.1058C>T	p.Pro353Leu	missense	Exon 13 of 41	ENSP00000632720.1
	TRDN	ENST00000962654.1		c.1058C>T	p.Pro353Leu	missense	Exon 13 of 41	ENSP00000632713.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151764 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000765 AC: 18 AN: 235388 AF XY: 0.0000940

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000302

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000230

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000105

Gnomad OTH exome AF: 0.000174

GnomAD4 exome AF: 0.0000551 AC: 80 AN: 1452376 Hom.: 0 Cov.: 30 AF XY: 0.0000540 AC XY: 39 AN XY: 721852

African (AFR) AF: 0.00 AC: 0 AN: 33294

American (AMR) AF: 0.0000229 AC: 1 AN: 43730

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25798

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39538

South Asian (SAS) AF: 0.0000824 AC: 7 AN: 84932

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.0000533 AC: 59 AN: 1106562

Other (OTH) AF: 0.0000667 AC: 4 AN: 59936

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151764 Hom.: 0 Cov.: 32 AF XY: 0.0000405 AC XY: 3 AN XY: 74108

African (AFR) AF: 0.00 AC: 0 AN: 41308

American (AMR) AF: 0.00 AC: 0 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

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

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67920

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.0000194 Hom.: 0

Bravo AF: 0.000121

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000149 AC: 18

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	1	-	Catecholaminergic polymorphic ventricular tachycardia 1 (1)
-	1	-	Catecholaminergic polymorphic ventricular tachycardia 1;C3809536:Catecholaminergic polymorphic ventricular tachycardia 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		2.6
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.051
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.17	T
Polyphen		0.021	B
Vest4		0.26
MutPred		0.18		Gain of MoRF binding (P = 0.0474)
MVP		0.26
ClinPred		0.084	T
GERP RS		2.3
Varity_R		0.055
gMVP		0.015
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs754708708; hg19: chr6-123714819; COSMIC: COSV62125970;