rs201021891

chr6-123548478-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_006073.4(TRDN):c.367G>A(p.Asp123Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000334 in 1,572,536 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00033 (1 hom.)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:5
• Conservation: PhyloP100: 3.85

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.004431665).
• BP6: Variant 6-123548478-C-T is Benign according to our data. Variant chr6-123548478-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 264130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRDN	NM_006073.4	c.367G>A	p.Asp123Asn	missense_variant	3/41	ENST00000334268.9
LOC105377982	XR_001743833.2	n.2346-4878C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRDN	ENST00000334268.9	c.367G>A	p.Asp123Asn	missense_variant	3/41	1	NM_006073.4	A2
	ENST00000648704.1	n.449-4944C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000336 AC: 51 AN: 151894 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000679 AC: 140 AN: 206190 Hom.: 0 AF XY: 0.000574 AC XY: 64 AN XY: 111460

Gnomad AFR exome AF: 0.0000790

Gnomad AMR exome AF: 0.000182

Gnomad ASJ exome AF: 0.0136

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000140

Gnomad OTH exome AF: 0.00101

GnomAD4 exome AF: 0.000334 AC: 475 AN: 1420642 Hom.: 1 Cov.: 35 AF XY: 0.000336 AC XY: 237 AN XY: 704412

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000389

Gnomad4 ASJ exome AF: 0.0140

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000586

Gnomad4 OTH exome AF: 0.000854

GnomAD4 genome AF: 0.000336 AC: 51 AN: 151894 Hom.: 0 Cov.: 31 AF XY: 0.000324 AC XY: 24 AN XY: 74174

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000657

Gnomad4 ASJ AF: 0.0124

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000442

Gnomad4 OTH AF: 0.00192

Alfa AF: 0.000759 Hom.: 2

Bravo AF: 0.000431

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000266 AC: 1

ESP6500EA AF: 0.000486 AC: 4

ExAC AF: 0.000399 AC: 48

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2020	This variant is associated with the following publications: (PMID: 31341780) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	TRDN: BP4, BS1, BS2 -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	May 22, 2017	This patient is a 14-year old female with a history of chronic dizziness and one episode of VT detected on Holter. She had an Arrhythmia and Cardiomyopathy Comprehensive Panel with the Invitae Laboratory. The following genes were evaluated for sequence changes and exonic deletions/duplications: ABCC9, ACTC1, ACTN2, AGL, AKAP9, ANK2, ANKRD1, BAG3, CACNA1C, CACNA2D1, CACNB2, CALM1, CALM2, CALM3, CALR3, CASQ2, CAV3, CHRM2, CRYAB, CSRP3, CTF1, CTNNA3, DES, DMD, DOLK, DSC2, DSG2, DSP, DTNA, EMD, EYA4, FHL1, FHL2, FKRP, FKTN, FLNC, GAA, GATA4, GATA6, GATAD1, GJA5, GLA, GPD1L, HCN4, ILK, JPH2, JUP, KCNA5, KCND3, KCNE1, KCNE2, KCNE3, KCNE5, KCNH2, KCNJ2, KCNJ5, KCNJ8, KCNK3, KCNQ1, LAMA4, LAMP2, LDB3, LMNA, LRRC10, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYL4, MYLK2, MYOM1, MYOZ2, MYPN, NEBL, NEXN, NKX2-5, NPPA, PDLIM3, PKP2, PLEKHM2, PLN, PRDM16, PRKAG2, RAF1, RANGRF, RBM20, RYR2, SCN10A, SCN1B, SCN2B, SCN3B, SCN4B, SCN5A, SGCD, SLC22A5, SLMAP, SNTA1, TAZ, TCAP, TGFB3, TMEM43, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TRDN, TRPM4, TTN, TTR, TXNRD2, VCL. Results indicate that two variants were detected: p.Asp123Asn (D123N; c.367G>A) in the TRDN gene p.Arg696Cys (c.2086C>T) in the MYOM1 gene We do not currently suspect that either of these is the cause of her episodes of dizziness and VT. p.Asp123Asn (D123N; c.367G>A) in exon 3 of the TRDN gene (NM_006073.3) Chromosome position 6:123869623 C / T The TRDN gene causes an autosomal recessive form of LQTS and CPVT. No second variant was reported in the patient’s other TRDN allele. Invitae classifies p.Asp123Asn as a Variant of Uncertain Signficance (VUS). As of 5/22/2017 it has been reported to ClinVar as a VUS by Ambry, GeneDx, and Illumina as well. Based on the information reviewed below, including its high frequency among the Ashkenazi Jewish population, and the fact that it is not a truncating mutation, we classify it as a VUS, probably benign, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for diagnosis or predictive genetic testing. This variant has not previously been reported in the literature in association with disease. Typically, pathogenic TRDN variants are truncating (frameshift, splice site, or nonsense) rather than a missense variant such as this one. This is a nonconservative amino acid change, resulting in the replacement of a negatively-charged Aspartic Acid with a polar Asparagine. Aspartic Acid at this location is not conserved across ~100 vertebrate species for which we have data, and a Glutamic Acid (with similar properties) at this site is equally likely. The adjacent residues are also not conserved. There is currently no missense variation at nearby residues (+/- 10 amino acids) listed in ClinVar as Likely Pathogenic or Pathogenic. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Unknown"; AlignGVGD: "Class C0"). This variant was reported in 141 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Overall allele frequency 0.06%. Specifically, the variant was observed in 117/4,326 people with Ashkenazi Jewish ancestry (for the highest allele frequency: 1.35%), and also in 11/53,136 people with European (non-Finnish) ancestry for allele frequency 0.01%, as well as in 4 Latinos, 1 African-ancestry, and 8 “other” individuals. There are also 5 individuals with an in-frame deletion of Asp123 in gnomAD. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. Our patient’s ancestry -

Catecholaminergic polymorphic ventricular tachycardia 1;C3809536:Catecholaminergic polymorphic ventricular tachycardia 5 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 20, 2022

- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2017

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	0.10
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.25	T;.;.;.
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.76	T;T;T;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.0044	T;T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.1	M;M;.;M
MutationTaster	Benign	0.95	N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.7	N;.;N;N
REVEL	Benign	0.18
Sift	Uncertain	0.0070	D;.;D;T
Sift4G	Benign	0.33	T;T;T;T
Polyphen		0.64	P;.;.;.
Vest4		0.17
MVP		0.49
ClinPred		0.022	T
GERP RS		5.1
Varity_R		0.16
gMVP		0.022

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: rs201021891; hg19: chr6-123869623;