rs192289289

Positions:

chr6-123547361-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006073.4(TRDN):c.403G>A(p.Glu135Lys) variant causes a missense change. The variant allele was found at a frequency of 0.01 in 1,458,352 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. E135E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0085 ( 6 hom., cov: 32)

Exomes 𝑓: 0.010 ( 82 hom. )

Consequence

TRDN
NM_006073.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.76

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:

(HGNC:):

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=0.008121401).

BP6

Variant 6-123547361-C-T is Benign according to our data. Variant chr6-123547361-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 227120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-123547361-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00849 (1289/151898) while in subpopulation NFE AF= 0.0148 (1005/67906). AF 95% confidence interval is 0.014. There are 6 homozygotes in gnomad4. There are 580 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRDN	NM_006073.4 linkuse as main transcript	c.403G>A	p.Glu135Lys	missense_variant	4/41	ENST00000334268.9
LOC105377982	XR_001743833.2 linkuse as main transcript	n.2346-5995C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRDN	ENST00000334268.9 linkuse as main transcript	c.403G>A	p.Glu135Lys	missense_variant	4/41	1	NM_006073.4	A2	Q13061-1
	ENST00000648704.1 linkuse as main transcript	n.449-6061C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00849

AC:

1289

AN:

151780

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00285

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00440

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00674

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0148

Gnomad OTH

AF:

0.00719

GnomAD3 exomes

AF:

0.00692

AC:

782

AN:

113040

Hom.:

AF XY:

0.00690

AC XY:

415

AN XY:

60116

show subpopulations

Gnomad AFR exome

AF:

0.00272

Gnomad AMR exome

AF:

0.00160

Gnomad ASJ exome

AF:

0.000435

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00176

Gnomad FIN exome

AF:

0.00790

Gnomad NFE exome

AF:

0.0119

Gnomad OTH exome

AF:

0.00695

GnomAD4 exome

AF:

0.0102

AC:

13360

AN:

1306454

Hom.:

Cov.:

AF XY:

0.00992

AC XY:

6382

AN XY:

643240

show subpopulations

Gnomad4 AFR exome

AF:

0.00165

Gnomad4 AMR exome

AF:

0.00163

Gnomad4 ASJ exome

AF:

0.000388

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00155

Gnomad4 FIN exome

AF:

0.00818

Gnomad4 NFE exome

AF:

0.0120

Gnomad4 OTH exome

AF:

0.00720

GnomAD4 genome

AF:

0.00849

AC:

1289

AN:

151898

Hom.:

Cov.:

AF XY:

0.00781

AC XY:

580

AN XY:

74224

show subpopulations

Gnomad4 AFR

AF:

0.00285

Gnomad4 AMR

AF:

0.00440

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00674

Gnomad4 NFE

AF:

0.0148

Gnomad4 OTH

AF:

0.00712

Alfa

AF:

0.0118

Hom.:

Bravo

AF:

0.00763

TwinsUK

AF:

0.0111

AC:

ALSPAC

AF:

0.0163

AC:

ESP6500AA

AF:

0.00294

AC:

ESP6500EA

AF:

0.00991

AC:

ExAC

AF:

0.00360

AC:

373

Asia WGS

AF:

0.000584

AC:

AN:

3440

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	GeneDx	Sep 28, 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 14, 2015	p.Glu135Lys in exon 4 of TRDN: This variant is not expected to have clinical sig nificance because it has been identified in 1.3% (118/8804) of European chromoso mes including 1 homozygous individual by the Exome Aggregation Consortium (http: //exac.broadinstitute.org/; dbSNP rs192289289). -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2024

TRDN: BS1, BS2 -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 22, 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

Oct 10, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

T;.;.;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.88

D;D;D;D

MetaRNN

Benign

0.0081

T;T;T;T

MetaSVM

Benign

-0.60

MutationAssessor

Uncertain

2.1

M;M;.;M

MutationTaster

Benign

0.53

D;D;D;N

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.1

N;.;N;N

REVEL

Benign

0.25

Sift

Uncertain

0.0070

D;.;D;D

Sift4G

Benign

0.32

T;T;T;T

Polyphen

1.0

D;.;.;.

Vest4

0.29

MVP

0.68

ClinPred

0.0062

GERP RS

5.7

Varity_R

0.22

gMVP

0.023

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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