rs6902416

Variant names:

• chr6-123512312-G-C
• rs6902416
• NM_006073.4:c.601C>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.601C>G​(p.Leu201Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.859 in 1,475,352 control chromosomes in the GnomAD database, including 546,877 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 Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L201P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.85 (54736 hom., cov: 32)
  • Exomes 𝑓: 0.86 (492141 hom.)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.20
• Publications: 26 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=8.0956585E-7).
• BP6: Variant 6-123512312-G-C is Benign according to our data. Variant chr6-123512312-G-C is described in ClinVar as Benign. ClinVar VariationId is 227123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.862 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.601C>G	p.Leu201Val	missense	Exon 7 of 41	NP_006064.2	Q13061-1
	TRDN	NM_001251987.2		c.601C>G	p.Leu201Val	missense	Exon 7 of 21	NP_001238916.1	A0A590UJV0
	TRDN	NM_001407315.1		c.601C>G	p.Leu201Val	missense	Exon 7 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.601C>G	p.Leu201Val	missense	Exon 7 of 41	ENSP00000333984.5	Q13061-1
	TRDN	ENST00000628709.2	TSL:1	c.601C>G	p.Leu201Val	missense	Exon 7 of 9	ENSP00000486095.1	Q13061-2
	TRDN	ENST00000546248.6	TSL:1	c.601C>G	p.Leu201Val	missense	Exon 7 of 8	ENSP00000439281.2	H9ME53

Frequencies

GnomAD3 genomes AF: 0.848 AC: 128902 AN: 152002 Hom.: 54705 Cov.: 32

Gnomad AFR AF: 0.801

Gnomad AMI AF: 0.887

Gnomad AMR AF: 0.874

Gnomad ASJ AF: 0.818

Gnomad EAS AF: 0.883

Gnomad SAS AF: 0.843

Gnomad FIN AF: 0.875

Gnomad MID AF: 0.807

Gnomad NFE AF: 0.866

Gnomad OTH AF: 0.852

GnomAD2 exomes AF: 0.845 AC: 164187 AN: 194390 AF XY: 0.841

Gnomad AFR exome AF: 0.776

Gnomad AMR exome AF: 0.874

Gnomad ASJ exome AF: 0.808

Gnomad EAS exome AF: 0.877

Gnomad FIN exome AF: 0.860

Gnomad NFE exome AF: 0.847

Gnomad OTH exome AF: 0.861

GnomAD4 exome AF: 0.861 AC: 1139075 AN: 1323232 Hom.: 492141 Cov.: 25 AF XY: 0.859 AC XY: 565678 AN XY: 658342

African (AFR) AF: 0.788 AC: 23971 AN: 30416

American (AMR) AF: 0.876 AC: 32676 AN: 37288

Ashkenazi Jewish (ASJ) AF: 0.814 AC: 19639 AN: 24136

East Asian (EAS) AF: 0.889 AC: 33582 AN: 37776

South Asian (SAS) AF: 0.830 AC: 62592 AN: 75370

European-Finnish (FIN) AF: 0.868 AC: 43483 AN: 50110

Middle Eastern (MID) AF: 0.809 AC: 4343 AN: 5366

European-Non Finnish (NFE) AF: 0.865 AC: 871951 AN: 1007794

Other (OTH) AF: 0.852 AC: 46838 AN: 54976

GnomAD4 genome AF: 0.848 AC: 128981 AN: 152120 Hom.: 54736 Cov.: 32 AF XY: 0.847 AC XY: 62973 AN XY: 74362

African (AFR) AF: 0.800 AC: 33204 AN: 41504

American (AMR) AF: 0.874 AC: 13346 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.818 AC: 2840 AN: 3470

East Asian (EAS) AF: 0.884 AC: 4569 AN: 5170

South Asian (SAS) AF: 0.842 AC: 4064 AN: 4826

European-Finnish (FIN) AF: 0.875 AC: 9237 AN: 10560

Middle Eastern (MID) AF: 0.789 AC: 232 AN: 294

European-Non Finnish (NFE) AF: 0.866 AC: 58874 AN: 68002

Other (OTH) AF: 0.854 AC: 1806 AN: 2114

Alfa AF: 0.854 Hom.: 17993

Bravo AF: 0.844

TwinsUK AF: 0.862 AC: 3196

ALSPAC AF: 0.876 AC: 3375

ESP6500AA AF: 0.799 AC: 2828

ESP6500EA AF: 0.861 AC: 6904

ExAC AF: 0.826 AC: 96620

Asia WGS AF: 0.844 AC: 2928 AN: 3466

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	1.3
DANN	Benign	0.21
DEOGEN2	Benign	0.075	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0029	N
LIST_S2	Benign	0.049	T
MetaRNN	Benign	8.1e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.2	N
PhyloP100		-1.2
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.046
Sift	Benign	1.0	T
Sift4G	Benign	0.36	T
Polyphen		0.0	B
Vest4		0.014
ClinPred		0.000013	T
GERP RS		-3.4
Varity_R		0.035
gMVP		0.00083
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: rs6902416; hg19: chr6-123833457; COSMIC: COSV62125755; COSMIC: COSV62125755;