6-123375621-G-T

Position:

chr6-123375621-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.1257C>A(p.Asp419Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,515,306 control chromosomes in the GnomAD database, including 13,481 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 0.17 ( 2674 hom., cov: 33)

Exomes 𝑓: 0.12 ( 10807 hom. )

Consequence

TRDN
NM_006073.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.616

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=0.0029345155).

BP6

Variant 6-123375621-G-T is Benign according to our data. Variant chr6-123375621-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 227108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-123375621-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.289 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.1257C>A	p.Asp419Glu	missense_variant	19/41	ENST00000334268.9	NP_006064.2	Q13061-1
TRDN	NM_001251987.2 linkuse as main transcript	c.1260C>A	p.Asp420Glu	missense_variant	19/21		NP_001238916.1	A0A590UJV0Q8IVK2
TRDN	NM_001407315.1 linkuse as main transcript	c.1200C>A	p.Asp400Glu	missense_variant	18/20		NP_001394244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9 linkuse as main transcript	c.1257C>A	p.Asp419Glu	missense_variant	19/41	1	NM_006073.4	ENSP00000333984.5		Q13061-1
TRDN	ENST00000662930.1 linkuse as main transcript	c.1260C>A	p.Asp420Glu	missense_variant	19/21			ENSP00000499585.1		A0A590UJV0

Frequencies

GnomAD3 genomes

AF:

0.173

AC:

26317

AN:

151866

Hom.:

2659

Cov.:

show subpopulations

Gnomad AFR

AF:

0.293

Gnomad AMI

AF:

0.200

Gnomad AMR

AF:

0.138

Gnomad ASJ

AF:

0.136

Gnomad EAS

AF:

0.0648

Gnomad SAS

AF:

0.0703

Gnomad FIN

AF:

0.152

Gnomad MID

AF:

0.158

Gnomad NFE

AF:

0.129

Gnomad OTH

AF:

0.172

GnomAD3 exomes

AF:

0.114

AC:

16029

AN:

141010

Hom.:

1106

AF XY:

0.109

AC XY:

8157

AN XY:

74658

show subpopulations

Gnomad AFR exome

AF:

0.258

Gnomad AMR exome

AF:

0.100

Gnomad ASJ exome

AF:

0.132

Gnomad EAS exome

AF:

0.0510

Gnomad SAS exome

AF:

0.0603

Gnomad FIN exome

AF:

0.146

Gnomad NFE exome

AF:

0.119

Gnomad OTH exome

AF:

0.107

GnomAD4 exome

AF:

0.118

AC:

161008

AN:

1363324

Hom.:

10807

Cov.:

AF XY:

0.117

AC XY:

78715

AN XY:

672696

show subpopulations

Gnomad4 AFR exome

AF:

0.279

Gnomad4 AMR exome

AF:

0.107

Gnomad4 ASJ exome

AF:

0.134

Gnomad4 EAS exome

AF:

0.0475

Gnomad4 SAS exome

AF:

0.0653

Gnomad4 FIN exome

AF:

0.144

Gnomad4 NFE exome

AF:

0.118

Gnomad4 OTH exome

AF:

0.130

GnomAD4 genome

AF:

0.174

AC:

26374

AN:

151982

Hom.:

2674

Cov.:

AF XY:

0.173

AC XY:

12841

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.294

Gnomad4 AMR

AF:

0.138

Gnomad4 ASJ

AF:

0.136

Gnomad4 EAS

AF:

0.0642

Gnomad4 SAS

AF:

0.0703

Gnomad4 FIN

AF:

0.152

Gnomad4 NFE

AF:

0.129

Gnomad4 OTH

AF:

0.171

Alfa

AF:

0.130

Hom.:

2784

Bravo

AF:

0.179

TwinsUK

AF:

0.129

AC:

478

ALSPAC

AF:

0.119

AC:

459

ESP6500AA

AF:

0.257

AC:

908

ESP6500EA

AF:

0.119

AC:

949

ExAC

AF:

0.0664

AC:

6439

Asia WGS

AF:

0.117

AC:

404

AN:

3472

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	Apr 09, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Asp419Glu in exon 19 of TRDN: This variant is not expected to have clinical sign ificance because it has been identified in 25.7% (908/3534) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs17737379). -

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

Apr 21, 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

0.064

BayesDel_addAF

Benign

-0.84

BayesDel_noAF

Benign

-0.83

CADD

Benign

6.9

DANN

Benign

0.43

DEOGEN2

Benign

0.063

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.20

MetaRNN

Benign

0.0029

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-0.81

PrimateAI

Benign

0.43

PROVEAN

Benign

0.22

REVEL

Benign

0.069

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.029

MutPred

0.23

Loss of MoRF binding (P = 0.0942);

ClinPred

0.0055

GERP RS

4.1

Varity_R

0.032

gMVP

0.0026

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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