rs28494009

Positions:

chr6-123377874-A-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.1211T>G(p.Val404Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 1,533,254 control chromosomes in the GnomAD database, including 18,325 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 0.16 ( 2175 hom., cov: 32)

Exomes 𝑓: 0.15 ( 16150 hom. )

Consequence

TRDN
NM_006073.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.0250

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=0.0028282404).

BP6

Variant 6-123377874-A-C is Benign according to our data. Variant chr6-123377874-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 227107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-123377874-A-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.21 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TRDN	NM_006073.4 linkuse as main transcript	c.1211T>G	p.Val404Gly	missense_variant	17/41	ENST00000334268.9	NP_006064.2
TRDN	NM_001251987.2 linkuse as main transcript	c.1214T>G	p.Val405Gly	missense_variant	17/21		NP_001238916.1
TRDN	NM_001407315.1 linkuse as main transcript	c.1154T>G	p.Val385Gly	missense_variant	16/20		NP_001394244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9 linkuse as main transcript	c.1211T>G	p.Val404Gly	missense_variant	17/41	1	NM_006073.4	ENSP00000333984	A2	Q13061-1
TRDN	ENST00000662930.1 linkuse as main transcript	c.1214T>G	p.Val405Gly	missense_variant	17/21			ENSP00000499585

Frequencies

GnomAD3 genomes

AF:

0.164

AC:

24966

AN:

152002

Hom.:

2175

Cov.:

show subpopulations

Gnomad AFR

AF:

0.201

Gnomad AMI

AF:

0.238

Gnomad AMR

AF:

0.110

Gnomad ASJ

AF:

0.0806

Gnomad EAS

AF:

0.0785

Gnomad SAS

AF:

0.221

Gnomad FIN

AF:

0.198

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.156

Gnomad OTH

AF:

0.134

GnomAD3 exomes

AF:

0.152

AC:

28782

AN:

188752

Hom.:

2432

AF XY:

0.158

AC XY:

16056

AN XY:

101424

show subpopulations

Gnomad AFR exome

AF:

0.204

Gnomad AMR exome

AF:

0.0829

Gnomad ASJ exome

AF:

0.0821

Gnomad EAS exome

AF:

0.0834

Gnomad SAS exome

AF:

0.237

Gnomad FIN exome

AF:

0.197

Gnomad NFE exome

AF:

0.152

Gnomad OTH exome

AF:

0.131

GnomAD4 exome

AF:

0.148

AC:

203831

AN:

1381138

Hom.:

16150

Cov.:

AF XY:

0.151

AC XY:

103345

AN XY:

686038

show subpopulations

Gnomad4 AFR exome

AF:

0.195

Gnomad4 AMR exome

AF:

0.0839

Gnomad4 ASJ exome

AF:

0.0820

Gnomad4 EAS exome

AF:

0.0651

Gnomad4 SAS exome

AF:

0.228

Gnomad4 FIN exome

AF:

0.197

Gnomad4 NFE exome

AF:

0.145

Gnomad4 OTH exome

AF:

0.139

GnomAD4 genome

AF:

0.164

AC:

24961

AN:

152116

Hom.:

2175

Cov.:

AF XY:

0.165

AC XY:

12257

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.201

Gnomad4 AMR

AF:

0.109

Gnomad4 ASJ

AF:

0.0806

Gnomad4 EAS

AF:

0.0779

Gnomad4 SAS

AF:

0.221

Gnomad4 FIN

AF:

0.198

Gnomad4 NFE

AF:

0.156

Gnomad4 OTH

AF:

0.133

Alfa

AF:

0.145

Hom.:

2594

Bravo

AF:

0.156

TwinsUK

AF:

0.155

AC:

573

ALSPAC

AF:

0.166

AC:

640

ESP6500AA

AF:

0.189

AC:

671

ESP6500EA

AF:

0.145

AC:

1178

ExAC

AF:

0.137

AC:

15894

Asia WGS

AF:

0.155

AC:

541

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Val404Gly in exon 17 of TRDN: This variant is not expected to have clinical sign ificance because it has been identified in 18.9% (671/3550) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs28494009). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 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	Apr 10, 2023	- -

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

Mar 23, 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

0.11

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.27

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.36

REVEL

Benign

0.024

Sift

Uncertain

0.0050

Sift4G

Benign

0.37

Polyphen

0.047

Vest4

0.080

ClinPred

0.018

GERP RS

-0.35

Varity_R

0.13

gMVP

0.016

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