6-123375621-G-T

Variant names:

• chr6-123375621-G-T
• rs17737379
• NM_006073.4:c.1257C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006073.4(TRDN):​c.1257C>A​(p.Asp419Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,515,306 control chromosomes in the GnomAD database, including 13,481 homozygotes. 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 Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.17 (2674 hom., cov: 33)
  • Exomes 𝑓: 0.12 (10807 hom.)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.616
• Publications: 15 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029345155).
• BP6: Variant 6-123375621-G-T is Benign according to our data. Variant chr6-123375621-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

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.1257C>A	p.Asp419Glu	missense	Exon 19 of 41	NP_006064.2	Q13061-1
	TRDN	NM_001251987.2		c.1260C>A	p.Asp420Glu	missense	Exon 19 of 21	NP_001238916.1	A0A590UJV0
	TRDN	NM_001407315.1		c.1200C>A	p.Asp400Glu	missense	Exon 18 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.1257C>A	p.Asp419Glu	missense	Exon 19 of 41	ENSP00000333984.5	Q13061-1
	TRDN	ENST00000962661.1		c.1260C>A	p.Asp420Glu	missense	Exon 19 of 41	ENSP00000632720.1
	TRDN	ENST00000962654.1		c.1257C>A	p.Asp419Glu	missense	Exon 19 of 41	ENSP00000632713.1

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26317 AN: 151866 Hom.: 2659 Cov.: 33

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.0648

Gnomad SAS AF: 0.0703

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.172

GnomAD2 exomes AF: 0.114 AC: 16029 AN: 141010 AF XY: 0.109

Gnomad AFR exome AF: 0.258

Gnomad AMR exome AF: 0.100

Gnomad ASJ exome AF: 0.132

Gnomad EAS exome AF: 0.0510

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.119

Gnomad OTH exome AF: 0.107

GnomAD4 exome AF: 0.118 AC: 161008 AN: 1363324 Hom.: 10807 Cov.: 29 AF XY: 0.117 AC XY: 78715 AN XY: 672696

African (AFR) AF: 0.279 AC: 8152 AN: 29262

American (AMR) AF: 0.107 AC: 3360 AN: 31532

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 3308 AN: 24616

East Asian (EAS) AF: 0.0475 AC: 1652 AN: 34798

South Asian (SAS) AF: 0.0653 AC: 4915 AN: 75226

European-Finnish (FIN) AF: 0.144 AC: 7036 AN: 48872

Middle Eastern (MID) AF: 0.154 AC: 840 AN: 5456

European-Non Finnish (NFE) AF: 0.118 AC: 124401 AN: 1056956

Other (OTH) AF: 0.130 AC: 7344 AN: 56606

GnomAD4 genome AF: 0.174 AC: 26374 AN: 151982 Hom.: 2674 Cov.: 33 AF XY: 0.173 AC XY: 12841 AN XY: 74268

African (AFR) AF: 0.294 AC: 12187 AN: 41478

American (AMR) AF: 0.138 AC: 2108 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 471 AN: 3468

East Asian (EAS) AF: 0.0642 AC: 332 AN: 5172

South Asian (SAS) AF: 0.0703 AC: 339 AN: 4820

European-Finnish (FIN) AF: 0.152 AC: 1603 AN: 10556

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.129 AC: 8742 AN: 67916

Other (OTH) AF: 0.171 AC: 360 AN: 2104

Alfa AF: 0.136 Hom.: 6038

Bravo AF: 0.179

TwinsUK AF: 0.129 AC: 478

ALSPAC AF: 0.119 AC: 459

ESP6500AA AF: 0.257 AC: 908

ESP6500EA AF: 0.119 AC: 949

ExAC AF: 0.0664 AC: 6439

Asia WGS AF: 0.117 AC: 404 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.9
DANN	Benign	0.43
DEOGEN2	Benign	0.063	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.81	N
PhyloP100		0.62
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.22	N
REVEL	Benign	0.069
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.029
MutPred		0.23		Loss of MoRF binding (P = 0.0942)
ClinPred		0.0055	T
GERP RS		4.1
Varity_R		0.032
gMVP		0.0026
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs17737379; hg19: chr6-123696766; COSMIC: COSV62127818;