6-123279062-G-T

Position:

chr6-123279062-G-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.1531C>A(p.Pro511Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000318 in 1,608,382 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0017 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

TRDN
NM_006073.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.231

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=0.004357159).

BP6

Variant 6-123279062-G-T is Benign according to our data. Variant chr6-123279062-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 415178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00166 (253/152132) while in subpopulation AFR AF= 0.00592 (246/41530). AF 95% confidence interval is 0.00532. There are 2 homozygotes in gnomad4. There are 112 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRDN	NM_006073.4 linkuse as main transcript	c.1531C>A	p.Pro511Thr	missense_variant	25/41	ENST00000334268.9	NP_006064.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9 linkuse as main transcript	c.1531C>A	p.Pro511Thr	missense_variant	25/41	1	NM_006073.4	ENSP00000333984	A2	Q13061-1

Frequencies

GnomAD3 genomes

AF:

0.00166

AC:

252

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00592

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000476

AC:

117

AN:

245812

Hom.:

AF XY:

0.000397

AC XY:

AN XY:

133442

show subpopulations

Gnomad AFR exome

AF:

0.00724

Gnomad AMR exome

AF:

0.000176

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000177

AC:

258

AN:

1456250

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

117

AN XY:

724310

show subpopulations

Gnomad4 AFR exome

AF:

0.00672

Gnomad4 AMR exome

AF:

0.000158

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.000349

GnomAD4 genome

AF:

0.00166

AC:

253

AN:

152132

Hom.:

Cov.:

AF XY:

0.00151

AC XY:

112

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00592

Gnomad4 AMR

AF:

0.000459

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000344

Hom.:

Bravo

AF:

0.00196

ESP6500AA

AF:

0.00495

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000555

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 14, 2018

p.Pro511Thr in exon 25 of TRDN: This variant is classified as benign because it has been identified in 0.7% (159/23872) of African chromosomes by the Genome Agg regation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs146935076). ACMG/AMP Criteria: BA1. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 06, 2020

- -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2018

This alteration is classified as likely 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

0.060

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.47

M_CAP

Benign

0.0052

MetaRNN

Benign

0.0044

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.34

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

0.27

REVEL

Benign

0.017

Sift

Pathogenic

0.0

Sift4G

Benign

0.11

Polyphen

0.0010

Vest4

0.16

MVP

0.088

ClinPred

0.026

GERP RS

2.5

Varity_R

0.11

gMVP

0.0061

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