6-123366143-A-C

Variant names:

• chr6-123366143-A-C
• rs2873479
• NM_006073.4:c.1313T>G

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.1313T>G​(p.Ile438Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.913 in 1,611,814 control chromosomes in the GnomAD database, including 672,491 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 Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I438N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.93 (65176 hom., cov: 32)
  • Exomes 𝑓: 0.91 (607315 hom.)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 2.38
• Publications: 30 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=8.387485E-7).
• BP6: Variant 6-123366143-A-C is Benign according to our data. Variant chr6-123366143-A-C is described in ClinVar as Benign. ClinVar VariationId is 227110.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.943 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.1313T>G	p.Ile438Ser	missense	Exon 20 of 41	NP_006064.2	Q13061-1
	TRDN	NM_001251987.2		c.1316T>G	p.Ile439Ser	missense	Exon 20 of 21	NP_001238916.1	A0A590UJV0
	TRDN	NM_001407315.1		c.1256T>G	p.Ile419Ser	missense	Exon 19 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.1313T>G	p.Ile438Ser	missense	Exon 20 of 41	ENSP00000333984.5	Q13061-1
	TRDN	ENST00000962661.1		c.1316T>G	p.Ile439Ser	missense	Exon 20 of 41	ENSP00000632720.1
	TRDN	ENST00000962654.1		c.1313T>G	p.Ile438Ser	missense	Exon 20 of 41	ENSP00000632713.1

Frequencies

GnomAD3 genomes AF: 0.925 AC: 140688 AN: 152080 Hom.: 65116 Cov.: 32

Gnomad AFR AF: 0.951

Gnomad AMI AF: 0.868

Gnomad AMR AF: 0.938

Gnomad ASJ AF: 0.905

Gnomad EAS AF: 0.920

Gnomad SAS AF: 0.940

Gnomad FIN AF: 0.922

Gnomad MID AF: 0.930

Gnomad NFE AF: 0.908

Gnomad OTH AF: 0.932

GnomAD2 exomes AF: 0.925 AC: 229675 AN: 248196 AF XY: 0.924

Gnomad AFR exome AF: 0.952

Gnomad AMR exome AF: 0.964

Gnomad ASJ exome AF: 0.908

Gnomad EAS exome AF: 0.915

Gnomad FIN exome AF: 0.928

Gnomad NFE exome AF: 0.909

Gnomad OTH exome AF: 0.927

GnomAD4 exome AF: 0.912 AC: 1331268 AN: 1459616 Hom.: 607315 Cov.: 37 AF XY: 0.912 AC XY: 662484 AN XY: 726108

African (AFR) AF: 0.953 AC: 31868 AN: 33446

American (AMR) AF: 0.965 AC: 43051 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.909 AC: 23719 AN: 26088

East Asian (EAS) AF: 0.925 AC: 36621 AN: 39588

South Asian (SAS) AF: 0.937 AC: 80659 AN: 86074

European-Finnish (FIN) AF: 0.925 AC: 49311 AN: 53290

Middle Eastern (MID) AF: 0.934 AC: 5374 AN: 5756

European-Non Finnish (NFE) AF: 0.906 AC: 1005539 AN: 1110452

Other (OTH) AF: 0.914 AC: 55126 AN: 60290

GnomAD4 genome AF: 0.925 AC: 140809 AN: 152198 Hom.: 65176 Cov.: 32 AF XY: 0.925 AC XY: 68844 AN XY: 74398

African (AFR) AF: 0.951 AC: 39467 AN: 41522

American (AMR) AF: 0.938 AC: 14347 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.905 AC: 3139 AN: 3470

East Asian (EAS) AF: 0.920 AC: 4745 AN: 5158

South Asian (SAS) AF: 0.940 AC: 4536 AN: 4824

European-Finnish (FIN) AF: 0.922 AC: 9777 AN: 10600

Middle Eastern (MID) AF: 0.939 AC: 276 AN: 294

European-Non Finnish (NFE) AF: 0.908 AC: 61756 AN: 68006

Other (OTH) AF: 0.933 AC: 1974 AN: 2116

Alfa AF: 0.915 Hom.: 173975

Bravo AF: 0.931

TwinsUK AF: 0.908 AC: 3366

ALSPAC AF: 0.899 AC: 3463

ESP6500AA AF: 0.948 AC: 3431

ESP6500EA AF: 0.916 AC: 7466

ExAC AF: 0.924 AC: 111543

EpiCase AF: 0.908

EpiControl AF: 0.907

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	Catecholaminergic polymorphic ventricular tachycardia 5 (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	17
DANN	Benign	0.69
DEOGEN2	Benign	0.064	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.23	T
MetaRNN	Benign	8.4e-7	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.4
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.52	N
REVEL	Benign	0.062
Sift	Benign	0.41	T
Sift4G	Benign	0.79	T
Polyphen		0.0	B
Vest4		0.015
ClinPred		0.0039	T
GERP RS		4.7
Varity_R		0.046
gMVP		0.0054
Mutation Taster		=100/0	polymorphism (auto)

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: rs2873479; hg19: chr6-123687288; COSMIC: COSV107392655;