6-123503847-A-C

Position:

• chr6-123503847-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006073.4(TRDN):​c.665T>G​(p.Val222Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000969 in 1,445,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000097 (0 hom.)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.16

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-AS1 (HGNC:40592): (TRDN antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14888501).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRDN	NM_006073.4	c.665T>G	p.Val222Gly	missense_variant	8/41	ENST00000334268.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRDN	ENST00000334268.9	c.665T>G	p.Val222Gly	missense_variant	8/41	1	NM_006073.4	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000913 AC: 2 AN: 218958 Hom.: 0 AF XY: 0.00000847 AC XY: 1 AN XY: 118064

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000210

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000969 AC: 14 AN: 1445500 Hom.: 0 Cov.: 32 AF XY: 0.00000976 AC XY: 7 AN XY: 717578

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000127

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000834 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 29, 2021

This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 222 of the TRDN protein (p.Val222Gly). This variant is present in population databases (rs758037868, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with TRDN-related conditions. ClinVar contains an entry for this variant (Variation ID: 463679). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2022

The c.665T>G (p.V222G) alteration is located in exon 8 (coding exon 8) of the TRDN gene. This alteration results from a T to G substitution at nucleotide position 665, causing the valine (V) at amino acid position 222 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Uncertain	0.46	T;.;.
Eigen	Benign	-0.078
Eigen_PC	Benign	-0.065
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.70	T;T;T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.3	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.5	D;.;N
REVEL	Benign	0.063
Sift	Uncertain	0.0010	D;.;T
Sift4G	Pathogenic	0.0010	D;T;T
Polyphen		0.0070	B;.;.
Vest4		0.24
MutPred		0.35		Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);
MVP		0.58
ClinPred		0.24	T
GERP RS		1.9
Varity_R		0.46
gMVP		0.015

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: rs758037868; hg19: chr6-123824992;