rs35766971

Positions:

chr6-123438098-C-T

Variant summary

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

The ENST00000334268.9(TRDN):c.1016G>A(p.Ser339Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00205 in 1,591,380 control chromosomes in the GnomAD database, including 72 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S339S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.011 ( 37 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 35 hom. )

Consequence

TRDN
ENST00000334268.9 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.92

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0023744404).

BP6

Variant 6-123438098-C-T is Benign according to our data. Variant chr6-123438098-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 227102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-123438098-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0114 (1736/152186) while in subpopulation AFR AF= 0.0385 (1599/41530). AF 95% confidence interval is 0.0369. There are 37 homozygotes in gnomad4. There are 793 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 37 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TRDN	NM_006073.4 linkuse as main transcript	c.1016G>A	p.Ser339Asn	missense_variant	12/41	ENST00000334268.9	NP_006064.2
TRDN	NM_001251987.2 linkuse as main transcript	c.1019G>A	p.Ser340Asn	missense_variant	12/21		NP_001238916.1
TRDN	NM_001407315.1 linkuse as main transcript	c.959G>A	p.Ser320Asn	missense_variant	11/20		NP_001394244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9 linkuse as main transcript	c.1016G>A	p.Ser339Asn	missense_variant	12/41	1	NM_006073.4	ENSP00000333984	A2	Q13061-1
TRDN-AS1	ENST00000587106.6 linkuse as main transcript	n.572-1505C>T		intron_variant, non_coding_transcript_variant		5
TRDN	ENST00000662930.1 linkuse as main transcript	c.1019G>A	p.Ser340Asn	missense_variant	12/21			ENSP00000499585

Frequencies

GnomAD3 genomes

AF:

0.0114

AC:

1734

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00733

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.00271

AC:

594

AN:

219566

Hom.:

AF XY:

0.00201

AC XY:

239

AN XY:

119004

show subpopulations

Gnomad AFR exome

AF:

0.0371

Gnomad AMR exome

AF:

0.00228

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000297

Gnomad OTH exome

AF:

0.00167

GnomAD4 exome

AF:

0.00107

AC:

1534

AN:

1439194

Hom.:

Cov.:

AF XY:

0.000887

AC XY:

634

AN XY:

714934

show subpopulations

Gnomad4 AFR exome

AF:

0.0386

Gnomad4 AMR exome

AF:

0.00296

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000764

Gnomad4 SAS exome

AF:

0.0000245

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000217

Gnomad4 OTH exome

AF:

0.00249

GnomAD4 genome

AF:

0.0114

AC:

1736

AN:

152186

Hom.:

Cov.:

AF XY:

0.0107

AC XY:

793

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.0385

Gnomad4 AMR

AF:

0.00739

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.00199

Hom.:

Bravo

AF:

0.0129

ESP6500AA

AF:

0.0334

AC:

123

ESP6500EA

AF:

0.000123

AC:

ExAC

AF:

0.00322

AC:

388

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 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	Nov 24, 2014	Ser340Asn in exon 12 of TRDN: This variant is not expected to have clinical sign ificance because it has been identified in 3.3% (123/3682) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs35766971). -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 15, 2024	- -

TRDN-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 29, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 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

Jun 19, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.42

MetaRNN

Benign

0.0024

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.29

REVEL

Benign

0.070

Sift

Uncertain

0.0080

Sift4G

Benign

0.48

Polyphen

0.089

Vest4

0.11

MVP

0.22

ClinPred

0.0060

GERP RS

3.7

Varity_R

0.079

gMVP

0.0055

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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