rs6569336

Positions:

chr6-123337631-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006073.4(TRDN):c.1408C>A(p.Leu470Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,422,180 control chromosomes in the GnomAD database, including 3,068 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.085 ( 1786 hom., cov: 32)

Exomes 𝑓: 0.010 ( 1282 hom. )

Consequence

TRDN
NM_006073.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.0770

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:

LOC105377984 (HGNC:):

LOC105377984 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0048668683).

BP6

Variant 6-123337631-G-T is Benign according to our data. Variant chr6-123337631-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 227112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-123337631-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRDN	NM_006073.4 linkuse as main transcript	c.1408C>A	p.Leu470Met	missense_variant	22/41	ENST00000334268.9	NP_006064.2	Q13061-1
LOC105377984	XR_942947.3 linkuse as main transcript	n.214-1G>T		splice_acceptor_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9 linkuse as main transcript	c.1408C>A	p.Leu470Met	missense_variant	22/41	1	NM_006073.4	ENSP00000333984.5		Q13061-1

Frequencies

GnomAD3 genomes

AF:

0.0851

AC:

12923

AN:

151898

Hom.:

1783

Cov.:

show subpopulations

Gnomad AFR

AF:

0.289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0303

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00174

Gnomad SAS

AF:

0.0639

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00118

Gnomad OTH

AF:

0.0628

GnomAD3 exomes

AF:

0.0247

AC:

3225

AN:

130400

Hom.:

313

AF XY:

0.0240

AC XY:

1662

AN XY:

69254

show subpopulations

Gnomad AFR exome

AF:

0.275

Gnomad AMR exome

AF:

0.0128

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00121

Gnomad SAS exome

AF:

0.0575

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00145

Gnomad OTH exome

AF:

0.0121

GnomAD4 exome

AF:

0.0105

AC:

13318

AN:

1270164

Hom.:

1282

Cov.:

AF XY:

0.0112

AC XY:

7009

AN XY:

628308

show subpopulations

Gnomad4 AFR exome

AF:

0.277

Gnomad4 AMR exome

AF:

0.0154

Gnomad4 ASJ exome

AF:

0.000216

Gnomad4 EAS exome

AF:

0.000686

Gnomad4 SAS exome

AF:

0.0577

Gnomad4 FIN exome

AF:

0.0000215

Gnomad4 NFE exome

AF:

0.000556

Gnomad4 OTH exome

AF:

0.0216

GnomAD4 genome

AF:

0.0852

AC:

12946

AN:

152016

Hom.:

1786

Cov.:

AF XY:

0.0821

AC XY:

6103

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.288

Gnomad4 AMR

AF:

0.0302

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00174

Gnomad4 SAS

AF:

0.0639

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00118

Gnomad4 OTH

AF:

0.0621

Alfa

AF:

0.0110

Hom.:

294

Bravo

AF:

0.0954

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.252

AC:

572

ESP6500EA

AF:

0.000800

AC:

ExAC

AF:

0.0460

AC:

1142

Asia WGS

AF:

0.0480

AC:

167

AN:

3470

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 20, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Leu470Met in exon 22 of TRDN: This variant is not expected to have clinical sign ificance because it has been identified in 25.2% (572/2268) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs6569336). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 08, 2016	- -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 15, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.054

LIST_S2

Benign

0.37

MetaRNN

Benign

0.0049

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.69

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.16

REVEL

Benign

0.021

Sift

Uncertain

0.019

Sift4G

Benign

0.15

Polyphen

0.61

Vest4

0.064

ClinPred

0.0031

GERP RS

0.78

Varity_R

0.082

gMVP

0.0093

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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