rs766406818

Variant names:

• chr6-123260635-C-G
• rs766406818
• NM_006073.4:c.1808G>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_006073.4(TRDN):​c.1808G>C​(p.Gly603Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000208 in 1,297,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000084 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -2.09
• Publications: 0 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

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026840955).
• BP6: Variant 6-123260635-C-G is Benign according to our data. Variant chr6-123260635-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 532357.

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.1808G>C	p.Gly603Ala	missense	Exon 34 of 41	NP_006064.2	Q13061-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRDN	ENST00000334268.9	TSL:1 MANE Select	c.1808G>C	p.Gly603Ala	missense	Exon 34 of 41	ENSP00000333984.5	Q13061-1
	TRDN	ENST00000962661.1		c.1811G>C	p.Gly604Ala	missense	Exon 34 of 41	ENSP00000632720.1
	TRDN	ENST00000962654.1		c.1808G>C	p.Gly603Ala	missense	Exon 34 of 41	ENSP00000632713.1

Frequencies

GnomAD3 genomes AF: 0.0000840 AC: 8 AN: 95236 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000166

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000246 AC: 2 AN: 81270 AF XY: 0.0000225

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000537

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000158 AC: 19 AN: 1202596 Hom.: 0 Cov.: 24 AF XY: 0.0000169 AC XY: 10 AN XY: 592862

African (AFR) AF: 0.00 AC: 0 AN: 25080

American (AMR) AF: 0.00 AC: 0 AN: 19090

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20000

East Asian (EAS) AF: 0.00 AC: 0 AN: 31514

South Asian (SAS) AF: 0.00 AC: 0 AN: 60310

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4056

European-Non Finnish (NFE) AF: 0.0000200 AC: 19 AN: 952280

Other (OTH) AF: 0.00 AC: 0 AN: 48942

GnomAD4 genome AF: 0.0000840 AC: 8 AN: 95236 Hom.: 0 Cov.: 29 AF XY: 0.0000650 AC XY: 3 AN XY: 46130

African (AFR) AF: 0.00 AC: 0 AN: 22876

American (AMR) AF: 0.00 AC: 0 AN: 8448

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2390

East Asian (EAS) AF: 0.00 AC: 0 AN: 3194

South Asian (SAS) AF: 0.00 AC: 0 AN: 2302

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5792

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 188

European-Non Finnish (NFE) AF: 0.000166 AC: 8 AN: 48106

Other (OTH) AF: 0.00 AC: 0 AN: 1220

Alfa AF: 0.0000602 Hom.: 0

ExAC AF: 0.0000423 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)
-	1	-	Catecholaminergic polymorphic ventricular tachycardia 1 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.0070
DANN	Benign	0.080
DEOGEN2	Benign	0.095	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.81	L
PhyloP100		-2.1
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.24	N
REVEL	Benign	0.0020
Sift	Benign	0.26	T
Sift4G	Benign	0.30	T
Polyphen		0.0	B
Vest4		0.065
MVP		0.014
ClinPred		0.066	T
GERP RS		-2.8
Varity_R		0.035
gMVP		0.013
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs766406818; hg19: chr6-123581780;