rs200243235

Positions:

chr6-123352541-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_006073.4(TRDN):c.1367A>G(p.Gln456Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 1,611,392 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 5 hom. )

Consequence

TRDN
NM_006073.4 missense, splice_region

Scores

Splicing: ADA: 0.8442

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:5

Conservation

PhyloP100: 2.96

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013671964).

BP6

Variant 6-123352541-T-C is Benign according to our data. Variant chr6-123352541-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 229345.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4}. Variant chr6-123352541-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00129 (196/152054) while in subpopulation NFE AF= 0.00239 (162/67862). AF 95% confidence interval is 0.00209. There are 0 homozygotes in gnomad4. There are 87 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TRDN	NM_006073.4 linkuse as main transcript	c.1367A>G	p.Gln456Arg	missense_variant, splice_region_variant	21/41	ENST00000334268.9	NP_006064.2
TRDN	NM_001251987.2 linkuse as main transcript	c.1370A>G	p.Gln457Arg	missense_variant	21/21		NP_001238916.1
TRDN	NM_001407315.1 linkuse as main transcript	c.1310A>G	p.Gln437Arg	missense_variant	20/20		NP_001394244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9 linkuse as main transcript	c.1367A>G	p.Gln456Arg	missense_variant, splice_region_variant	21/41	1	NM_006073.4	ENSP00000333984	A2	Q13061-1
TRDN	ENST00000662930.1 linkuse as main transcript	c.1370A>G	p.Gln457Arg	missense_variant	21/21			ENSP00000499585

Frequencies

GnomAD3 genomes

AF:

0.00129

AC:

196

AN:

151936

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00239

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00119

AC:

294

AN:

247280

Hom.:

AF XY:

0.00128

AC XY:

172

AN XY:

134278

show subpopulations

Gnomad AFR exome

AF:

0.00104

Gnomad AMR exome

AF:

0.0000586

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00145

Gnomad FIN exome

AF:

0.000233

Gnomad NFE exome

AF:

0.00194

Gnomad OTH exome

AF:

0.00151

GnomAD4 exome

AF:

0.00209

AC:

3051

AN:

1459338

Hom.:

Cov.:

AF XY:

0.00210

AC XY:

1521

AN XY:

725906

show subpopulations

Gnomad4 AFR exome

AF:

0.000330

Gnomad4 AMR exome

AF:

0.000135

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00158

Gnomad4 FIN exome

AF:

0.000338

Gnomad4 NFE exome

AF:

0.00249

Gnomad4 OTH exome

AF:

0.00178

GnomAD4 genome

AF:

0.00129

AC:

196

AN:

152054

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.000626

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00239

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00198

Hom.:

Bravo

AF:

0.00124

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.00162

AC:

ESP6500EA

AF:

0.00281

AC:

ExAC

AF:

0.00122

AC:

147

EpiCase

AF:

0.00159

EpiControl

AF:

0.00190

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	TRDN: BP4 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2024	Reported in individuals with DCM and unexplained cardiac arrest; also described as p.(Q457R) (PMID: 32746448, 35352813); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 35932045, 23035052, 32746448, 35352813, 37937776) -

Catecholaminergic polymorphic ventricular tachycardia 5

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	KardioGenetik, Herz- und Diabeteszentrum NRW	Aug 30, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2023	The TRDN c.1367A>G; p.Gln456Arg variant (rs200243235), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 229345). This variant is found in the non-Finnish European population with an allele frequency of 0.2% (243/127,472 alleles) in the Genome Aggregation Database. The glutamine at codon 456 is weakly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the p.Gln456Arg variant is uncertain at this time. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 16, 2016

Variant classified as Uncertain Significance - Favor Benign. The p.Gln457Arg var iant in TRDN has not been previously reported in individuals with cardiomyopathy , but has been identified in 0.2% (111/65742) of European chromosomes by the Exo me Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs2002432 35). Computational prediction tools and conservation analysis do not provide str ong support for or against an impact to the protein. In summary, while the clini cal significance of the p.Gln457Arg variant is uncertain, its frequency suggests that it is more likely to be benign. -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2021

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

0.13

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.45

M_CAP

Benign

0.012

MetaRNN

Benign

0.014

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

MutationTaster

Benign

0.94

N;N

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.82

REVEL

Benign

0.054

Sift

Pathogenic

0.0

Sift4G

Benign

0.20

Polyphen

1.0

Vest4

0.32

MVP

0.10

ClinPred

0.057

GERP RS

4.4

Varity_R

0.40

gMVP

0.0056

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.84

dbscSNV1_RF

Benign

0.57

SpliceAI score (max)

0.13

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