chr6-123393674-G-A

Position:

chr6-123393674-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000334268.9(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. 15/21 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
ENST00000334268.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.63

Variant links:

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 links:

TRDN-AS1 (HGNC:40592): (TRDN antisense RNA 1)

TRDN-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TRDN	NM_006073.4 linkuse as main transcript	c.1055C>T	p.Pro352Leu	missense_variant	13/41	ENST00000334268.9	NP_006064.2
TRDN	NM_001251987.2 linkuse as main transcript	c.1058C>T	p.Pro353Leu	missense_variant	13/21		NP_001238916.1
TRDN	NM_001407315.1 linkuse as main transcript	c.998C>T	p.Pro333Leu	missense_variant	12/20		NP_001394244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9 linkuse as main transcript	c.1055C>T	p.Pro352Leu	missense_variant	13/41	1	NM_006073.4	ENSP00000333984	A2	Q13061-1
TRDN-AS1	ENST00000587106.6 linkuse as main transcript	n.55+4199G>A		intron_variant, non_coding_transcript_variant		5
TRDN	ENST00000662930.1 linkuse as main transcript	c.1058C>T	p.Pro353Leu	missense_variant	13/21			ENSP00000499585

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151764

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000765

AC:

AN:

235388

Hom.:

AF XY:

0.0000940

AC XY:

AN XY:

127680

show subpopulations

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 SAS exome

AF:

0.0000343

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000105

Gnomad OTH exome

AF:

0.000174

GnomAD4 exome

AF:

0.0000551

AC:

AN:

1452376

Hom.:

Cov.:

AF XY:

0.0000540

AC XY:

AN XY:

721852

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000229

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.0000824

Gnomad4 FIN exome

AF:

0.0000189

Gnomad4 NFE exome

AF:

0.0000533

Gnomad4 OTH exome

AF:

0.0000667

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151764

Hom.:

Cov.:

AF XY:

0.0000405

AC XY:

AN XY:

74108

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000442

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000194

Hom.:

Bravo

AF:

0.000121

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000149

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1;C3809536:Catecholaminergic polymorphic ventricular tachycardia 5

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 07, 2021

- -

Catecholaminergic polymorphic ventricular tachycardia 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 25, 2022

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 352 of the TRDN protein (p.Pro352Leu). This variant is present in population databases (rs754708708, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with TRDN-related conditions. ClinVar contains an entry for this variant (Variation ID: 1015507). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 10, 2023

The p.P352L variant (also known as c.1055C>T), located in coding exon 13 of the TRDN gene, results from a C to T substitution at nucleotide position 1055. The proline at codon 352 is replaced by leucine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.19

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.53

M_CAP

Benign

0.039

MetaRNN

Benign

0.048

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.1

REVEL

Benign

0.051

Sift

Uncertain

0.0020

Sift4G

Benign

0.17

Polyphen

0.021

Vest4

0.26

MutPred

0.18

Gain of MoRF binding (P = 0.0474);

MVP

0.26

ClinPred

0.084

GERP RS

2.3

Varity_R

0.055

gMVP

0.015

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over