chr6-123547345-T-C

Variant names:

• chr6-123547345-T-C
• rs200953683
• NM_006073.4:c.419A>G

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.419A>G​(p.Lys140Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,462,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 0.586
• 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

ENSG00000285691 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.018538743).
• BP6: Variant 6-123547345-T-C is Benign according to our data. Variant chr6-123547345-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 408730.

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.419A>G	p.Lys140Arg	missense	Exon 4 of 41	NP_006064.2	Q13061-1
	TRDN	NM_001251987.2		c.419A>G	p.Lys140Arg	missense	Exon 4 of 21	NP_001238916.1	A0A590UJV0
	TRDN	NM_001407315.1		c.419A>G	p.Lys140Arg	missense	Exon 4 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.419A>G	p.Lys140Arg	missense	Exon 4 of 41	ENSP00000333984.5	Q13061-1
	TRDN	ENST00000628709.2	TSL:1	c.419A>G	p.Lys140Arg	missense	Exon 4 of 9	ENSP00000486095.1	Q13061-2
	TRDN	ENST00000546248.6	TSL:1	c.419A>G	p.Lys140Arg	missense	Exon 4 of 8	ENSP00000439281.2	H9ME53

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152024 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000280

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000205 AC: 23 AN: 112082 AF XY: 0.000251

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000256

Gnomad ASJ exome AF: 0.000878

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.00104

GnomAD4 exome AF: 0.000169 AC: 222 AN: 1310482 Hom.: 0 Cov.: 25 AF XY: 0.000191 AC XY: 123 AN XY: 645044

African (AFR) AF: 0.0000734 AC: 2 AN: 27258

American (AMR) AF: 0.000478 AC: 11 AN: 23014

Ashkenazi Jewish (ASJ) AF: 0.00125 AC: 29 AN: 23216

East Asian (EAS) AF: 0.00 AC: 0 AN: 32764

South Asian (SAS) AF: 0.00 AC: 0 AN: 62750

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5424

European-Non Finnish (NFE) AF: 0.000166 AC: 172 AN: 1033476

Other (OTH) AF: 0.000147 AC: 8 AN: 54366

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152142 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74416

African (AFR) AF: 0.0000482 AC: 2 AN: 41534

American (AMR) AF: 0.000131 AC: 2 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000280 AC: 19 AN: 67954

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000328 Hom.: 0

Bravo AF: 0.000230

ExAC AF: 0.000115 AC: 12

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Catecholaminergic polymorphic ventricular tachycardia 1 (1)
-	1	-	Catecholaminergic polymorphic ventricular tachycardia 1;C3809536:Catecholaminergic polymorphic ventricular tachycardia 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.098	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.59
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.031
Sift	Benign	0.82	T
Sift4G	Benign	0.47	T
Polyphen		0.0010	B
Vest4		0.061
MVP		0.40
ClinPred		0.019	T
GERP RS		2.0
Varity_R		0.046
gMVP		0.0061
Mutation Taster		=89/11	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: rs200953683; hg19: chr6-123868490;