chr6-123393671-C-T

Position:

• chr6-123393671-C-T

Variant summary

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

The ENST00000334268.9(TRDN):​c.1058G>A​(p.Gly353Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TRDN ENST00000334268.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.89

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=0.08605471).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRDN	NM_006073.4	c.1058G>A	p.Gly353Glu	missense_variant	13/41	ENST00000334268.9	NP_006064.2
TRDN	NM_001251987.2	c.1061G>A	p.Gly354Glu	missense_variant	13/21		NP_001238916.1
TRDN	NM_001407315.1	c.1001G>A	p.Gly334Glu	missense_variant	12/20		NP_001394244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9	c.1058G>A	p.Gly353Glu	missense_variant	13/41	1	NM_006073.4	ENSP00000333984	A2
TRDN-AS1	ENST00000587106.6	n.55+4196C>T		intron_variant, non_coding_transcript_variant		5
TRDN	ENST00000662930.1	c.1061G>A	p.Gly354Glu	missense_variant	13/21			ENSP00000499585

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000422 AC: 1 AN: 237100 Hom.: 0 AF XY: 0.00000778 AC XY: 1 AN XY: 128594

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000300

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: 6.88e-7 AC: 1 AN: 1453752 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 722568

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000228

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 25, 2022

Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 353 of the TRDN protein (p.Gly353Glu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with TRDN-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.074
Sift	Uncertain	0.0030	D
Sift4G	Benign	1.0	T
Polyphen		0.036	B
Vest4		0.16
MutPred		0.27		Gain of solvent accessibility (P = 0.024);
MVP		0.22
ClinPred		0.28	T
GERP RS		4.4
Varity_R		0.080
gMVP		0.0074

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1230466120; hg19: chr6-123714816; COSMIC: COSV105225105;