rs1259355217

Variant names:

• chr6-123388542-T-C
• rs1259355217
• NM_006073.4:c.1115A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_006073.4(TRDN):​c.1115A>G​(p.Lys372Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,586,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 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 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.699
• 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 -1 ACMG points.

• BP6: Variant 6-123388542-T-C is Benign according to our data. Variant chr6-123388542-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 450750.

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.1115A>G	p.Lys372Arg	missense	Exon 14 of 41	NP_006064.2	Q13061-1
	TRDN	NM_001251987.2		c.1118A>G	p.Lys373Arg	missense	Exon 14 of 21	NP_001238916.1	A0A590UJV0
	TRDN	NM_001407315.1		c.1058A>G	p.Lys353Arg	missense	Exon 13 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.1115A>G	p.Lys372Arg	missense	Exon 14 of 41	ENSP00000333984.5	Q13061-1
	TRDN	ENST00000962661.1		c.1118A>G	p.Lys373Arg	missense	Exon 14 of 41	ENSP00000632720.1
	TRDN	ENST00000962654.1		c.1115A>G	p.Lys372Arg	missense	Exon 14 of 41	ENSP00000632713.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 32

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000476 AC: 1 AN: 210068 AF XY: 0.00000891

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: 0.0000110

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000404 AC: 58 AN: 1434318 Hom.: 0 Cov.: 30 AF XY: 0.0000408 AC XY: 29 AN XY: 710578

African (AFR) AF: 0.0000301 AC: 1 AN: 33196

American (AMR) AF: 0.00 AC: 0 AN: 41024

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25596

East Asian (EAS) AF: 0.00 AC: 0 AN: 39002

South Asian (SAS) AF: 0.00 AC: 0 AN: 82474

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51798

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.0000502 AC: 55 AN: 1096154

Other (OTH) AF: 0.0000337 AC: 2 AN: 59356

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74338

African (AFR) AF: 0.00 AC: 0 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

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	-	Catecholaminergic polymorphic ventricular tachycardia 5 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.087	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.70
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.052
Sift	Benign	0.45	T
Sift4G	Benign	0.20	T
Polyphen		0.0020	B
Vest4		0.075
MutPred		0.16		Loss of ubiquitination at K372 (P = 0.0309)
MVP		0.067
ClinPred		0.054	T
GERP RS		0.71
Varity_R		0.028
gMVP		0.0028
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.29		Position offset: 9

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

Other links and lift over

dbSNP: rs1259355217; hg19: chr6-123709687;