6-123548568-G-T

Variant names:

• chr6-123548568-G-T
• rs370788759
• NM_006073.4:c.277C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_006073.4(TRDN):​c.277C>A​(p.Arg93Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000128 in 1,404,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R93C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.89
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• catecholaminergic polymorphic ventricular tachycardia 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• familial long QT syndrome

  Inheritance: AR Classification: STRONG Submitted by: G2P
• long QT syndrome

  Inheritance: AR Classification: STRONG Submitted by: ClinGen

ENSG00000285691 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12949023).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006073.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRDN	NM_006073.4	MANE Select	c.277C>A	p.Arg93Ser	missense	Exon 3 of 41	NP_006064.2	Q13061-1
	TRDN	NM_001251987.2		c.277C>A	p.Arg93Ser	missense	Exon 3 of 21	NP_001238916.1	A0A590UJV0
	TRDN	NM_001407315.1		c.277C>A	p.Arg93Ser	missense	Exon 3 of 20	NP_001394244.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRDN	ENST00000334268.9	TSL:1 MANE Select	c.277C>A	p.Arg93Ser	missense	Exon 3 of 41	ENSP00000333984.5	Q13061-1
	TRDN	ENST00000628709.2	TSL:1	c.277C>A	p.Arg93Ser	missense	Exon 3 of 9	ENSP00000486095.1	Q13061-2
	TRDN	ENST00000546248.6	TSL:1	c.277C>A	p.Arg93Ser	missense	Exon 3 of 8	ENSP00000439281.2	H9ME53

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000535 AC: 1 AN: 186764 AF XY: 0.00000996

Gnomad AFR exome AF: 0.0000905

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.0000128 AC: 18 AN: 1404408 Hom.: 0 Cov.: 35 AF XY: 0.0000158 AC XY: 11 AN XY: 695202

African (AFR) AF: 0.0000629 AC: 2 AN: 31786

American (AMR) AF: 0.00 AC: 0 AN: 37490

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24874

East Asian (EAS) AF: 0.0000267 AC: 1 AN: 37490

South Asian (SAS) AF: 0.00 AC: 0 AN: 76746

European-Finnish (FIN) AF: 0.0000393 AC: 2 AN: 50898

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5634

European-Non Finnish (NFE) AF: 0.0000120 AC: 13 AN: 1081546

Other (OTH) AF: 0.00 AC: 0 AN: 57944

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Catecholaminergic polymorphic ventricular tachycardia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.9
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.017
Sift	Benign	0.075	T
Sift4G	Benign	0.24	T
Polyphen		0.028	B
Vest4		0.13
MutPred		0.43		Gain of disorder (P = 0.0683)
MVP		0.19
ClinPred		0.087	T
GERP RS		3.3
Varity_R		0.11
gMVP		0.074
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs370788759; hg19: chr6-123869713;