rs7771303

Positions:

chr6-123273341-T-C

Variant summary

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

The NM_006073.4(TRDN):c.1620A>G(p.Ile540Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00714 in 1,054,006 control chromosomes in the GnomAD database, including 238 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 69 hom., cov: 32)

Exomes 𝑓: 0.0054 ( 169 hom. )

Consequence

TRDN
NM_006073.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.662

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:

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=0.0018236339).

BP6

Variant 6-123273341-T-C is Benign according to our data. Variant chr6-123273341-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 227115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-123273341-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.071 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRDN	NM_006073.4 linkuse as main transcript	c.1620A>G	p.Ile540Met	missense_variant	28/41	ENST00000334268.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRDN	ENST00000334268.9 linkuse as main transcript	c.1620A>G	p.Ile540Met	missense_variant	28/41	1	NM_006073.4	A2	Q13061-1

Frequencies

GnomAD3 genomes

AF:

0.0173

AC:

2619

AN:

151062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0443

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00557

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.0339

Gnomad SAS

AF:

0.0777

Gnomad FIN

AF:

0.00692

Gnomad MID

AF:

0.0130

Gnomad NFE

AF:

0.000944

Gnomad OTH

AF:

0.0135

GnomAD3 exomes

AF:

0.0151

AC:

1201

AN:

79470

Hom.:

AF XY:

0.0185

AC XY:

813

AN XY:

43970

show subpopulations

Gnomad AFR exome

AF:

0.0447

Gnomad AMR exome

AF:

0.00340

Gnomad ASJ exome

AF:

0.000200

Gnomad EAS exome

AF:

0.0412

Gnomad SAS exome

AF:

0.0683

Gnomad FIN exome

AF:

0.00591

Gnomad NFE exome

AF:

0.000703

Gnomad OTH exome

AF:

0.00549

GnomAD4 exome

AF:

0.00543

AC:

4906

AN:

902826

Hom.:

169

Cov.:

AF XY:

0.00749

AC XY:

3379

AN XY:

451238

show subpopulations

Gnomad4 AFR exome

AF:

0.0304

Gnomad4 AMR exome

AF:

0.00272

Gnomad4 ASJ exome

AF:

0.000464

Gnomad4 EAS exome

AF:

0.0155

Gnomad4 SAS exome

AF:

0.0618

Gnomad4 FIN exome

AF:

0.00503

Gnomad4 NFE exome

AF:

0.000402

Gnomad4 OTH exome

AF:

0.00635

GnomAD4 genome

AF:

0.0173

AC:

2618

AN:

151180

Hom.:

Cov.:

AF XY:

0.0190

AC XY:

1405

AN XY:

73816

show subpopulations

Gnomad4 AFR

AF:

0.0442

Gnomad4 AMR

AF:

0.00556

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.0339

Gnomad4 SAS

AF:

0.0776

Gnomad4 FIN

AF:

0.00692

Gnomad4 NFE

AF:

0.000944

Gnomad4 OTH

AF:

0.0133

Alfa

AF:

0.00512

Hom.:

Bravo

AF:

0.0162

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.0348

AC:

ESP6500EA

AF:

0.000901

AC:

ExAC

AF:

0.0228

AC:

690

Asia WGS

AF:

0.0580

AC:

202

AN:

3438

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Ile540Met in exon 28 of TRDN: This variant is not expected to have clinical sign ificance because it has been identified in 3.5% (86/2472) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs7771303). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 06, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 25, 2024	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

- -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 11, 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. -

Catecholaminergic polymorphic ventricular tachycardia 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 31, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.087

DANN

Benign

0.84

DEOGEN2

Benign

0.085

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.42

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.45

PROVEAN

Benign

0.29

REVEL

Benign

0.026

Sift

Uncertain

0.025

Sift4G

Benign

0.19

Polyphen

0.0040

Vest4

0.045

ClinPred

0.0041

GERP RS

-3.8

Varity_R

0.057

gMVP

0.0031

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