rs2873479

Positions:

• chr6-123366143-A-C
• chr6-123366143-A-G
• chr6-123366143-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006073.4(TRDN):​c.1313T>G​(p.Ile438Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.913 in 1,611,814 control chromosomes in the GnomAD database, including 672,491 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I438N) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.93 (65176 hom., cov: 32)
  • Exomes 𝑓: 0.91 (607315 hom.)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.38

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.387485E-7).
• BP6: Variant 6-123366143-A-C is Benign according to our data. Variant chr6-123366143-A-C is described in ClinVar as [Benign]. Clinvar id is 227110.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-123366143-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.943 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRDN	NM_006073.4	c.1313T>G	p.Ile438Ser	missense_variant	20/41	ENST00000334268.9	NP_006064.2
TRDN	NM_001251987.2	c.1316T>G	p.Ile439Ser	missense_variant	20/21		NP_001238916.1
TRDN	NM_001407315.1	c.1256T>G	p.Ile419Ser	missense_variant	19/20		NP_001394244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9	c.1313T>G	p.Ile438Ser	missense_variant	20/41	1	NM_006073.4	ENSP00000333984.5
TRDN	ENST00000662930.1	c.1316T>G	p.Ile439Ser	missense_variant	20/21			ENSP00000499585.1

Frequencies

GnomAD3 genomes AF: 0.925 AC: 140688 AN: 152080 Hom.: 65116 Cov.: 32

Gnomad AFR AF: 0.951

Gnomad AMI AF: 0.868

Gnomad AMR AF: 0.938

Gnomad ASJ AF: 0.905

Gnomad EAS AF: 0.920

Gnomad SAS AF: 0.940

Gnomad FIN AF: 0.922

Gnomad MID AF: 0.930

Gnomad NFE AF: 0.908

Gnomad OTH AF: 0.932

GnomAD3 exomes AF: 0.925 AC: 229675 AN: 248196 Hom.: 106346 AF XY: 0.924 AC XY: 124432 AN XY: 134654

Gnomad AFR exome AF: 0.952

Gnomad AMR exome AF: 0.964

Gnomad ASJ exome AF: 0.908

Gnomad EAS exome AF: 0.915

Gnomad SAS exome AF: 0.940

Gnomad FIN exome AF: 0.928

Gnomad NFE exome AF: 0.909

Gnomad OTH exome AF: 0.927

GnomAD4 exome AF: 0.912 AC: 1331268 AN: 1459616 Hom.: 607315 Cov.: 37 AF XY: 0.912 AC XY: 662484 AN XY: 726108

Gnomad4 AFR exome AF: 0.953

Gnomad4 AMR exome AF: 0.965

Gnomad4 ASJ exome AF: 0.909

Gnomad4 EAS exome AF: 0.925

Gnomad4 SAS exome AF: 0.937

Gnomad4 FIN exome AF: 0.925

Gnomad4 NFE exome AF: 0.906

Gnomad4 OTH exome AF: 0.914

GnomAD4 genome AF: 0.925 AC: 140809 AN: 152198 Hom.: 65176 Cov.: 32 AF XY: 0.925 AC XY: 68844 AN XY: 74398

Gnomad4 AFR AF: 0.951

Gnomad4 AMR AF: 0.938

Gnomad4 ASJ AF: 0.905

Gnomad4 EAS AF: 0.920

Gnomad4 SAS AF: 0.940

Gnomad4 FIN AF: 0.922

Gnomad4 NFE AF: 0.908

Gnomad4 OTH AF: 0.933

Alfa AF: 0.912 Hom.: 111556

Bravo AF: 0.931

TwinsUK AF: 0.908 AC: 3366

ALSPAC AF: 0.899 AC: 3463

ESP6500AA AF: 0.948 AC: 3431

ESP6500EA AF: 0.916 AC: 7466

ExAC AF: 0.924 AC: 111543

EpiCase AF: 0.908

EpiControl AF: 0.907

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Ile438Ser in exon 20 of TRDN: This variant is not expected to have clinical sign ificance because it has been identified in 8.4% (688/8154) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs2873479). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -

Catecholaminergic polymorphic ventricular tachycardia 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

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 09, 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	0.053
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	17
DANN	Benign	0.69
DEOGEN2	Benign	0.064	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.23	T
MetaRNN	Benign	8.4e-7	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.52	N
REVEL	Benign	0.062
Sift	Benign	0.41	T
Sift4G	Benign	0.79	T
Polyphen		0.0	B
Vest4		0.015
ClinPred		0.0039	T
GERP RS		4.7
Varity_R		0.046
gMVP		0.0054

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

Other links and lift over

dbSNP: rs2873479; hg19: chr6-123687288;