chr6-123393645-T-C

Position:

• chr6-123393645-T-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.1084A>G​(p.Thr362Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.257

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=0.08101183).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRDN	NM_006073.4	c.1084A>G	p.Thr362Ala	missense_variant	13/41	ENST00000334268.9	NP_006064.2
TRDN	NM_001251987.2	c.1087A>G	p.Thr363Ala	missense_variant	13/21		NP_001238916.1
TRDN	NM_001407315.1	c.1027A>G	p.Thr343Ala	missense_variant	12/20		NP_001394244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9	c.1084A>G	p.Thr362Ala	missense_variant	13/41	1	NM_006073.4	ENSP00000333984	A2
TRDN-AS1	ENST00000587106.6	n.55+4170T>C		intron_variant, non_coding_transcript_variant		5
TRDN	ENST00000662930.1	c.1087A>G	p.Thr363Ala	missense_variant	13/21			ENSP00000499585

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

TRDN NM_006073.3 exon 13 p.Thr362Ala (c.1084A>G): This variant has not been reported in the literature and is not present in large control databases. Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.081	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.066
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.50	T
Polyphen		0.43	B
Vest4		0.12
MutPred		0.17		Loss of phosphorylation at T362 (P = 0.0534);
MVP		0.21
ClinPred		0.19	T
GERP RS		4.1
Varity_R		0.14
gMVP		0.018

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-123714790;