rs201021891

Variant names:

• chr6-123548478-C-T
• rs201021891
• NM_006073.4:c.367G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_006073.4(TRDN):​c.367G>A​(p.Asp123Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000334 in 1,572,536 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00033 (1 hom.)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:5
• Conservation: PhyloP100: 3.85
• Publications: 4 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004431665).
• BP6: Variant 6-123548478-C-T is Benign according to our data. Variant chr6-123548478-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 264130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.367G>A	p.Asp123Asn	missense	Exon 3 of 41	NP_006064.2	Q13061-1
	TRDN	NM_001251987.2		c.367G>A	p.Asp123Asn	missense	Exon 3 of 21	NP_001238916.1	A0A590UJV0
	TRDN	NM_001407315.1		c.367G>A	p.Asp123Asn	missense	Exon 3 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.367G>A	p.Asp123Asn	missense	Exon 3 of 41	ENSP00000333984.5	Q13061-1
	TRDN	ENST00000628709.2	TSL:1	c.367G>A	p.Asp123Asn	missense	Exon 3 of 9	ENSP00000486095.1	Q13061-2
	TRDN	ENST00000546248.6	TSL:1	c.367G>A	p.Asp123Asn	missense	Exon 3 of 8	ENSP00000439281.2	H9ME53

Frequencies

GnomAD3 genomes AF: 0.000336 AC: 51 AN: 151894 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000679 AC: 140 AN: 206190 AF XY: 0.000574

Gnomad AFR exome AF: 0.0000790

Gnomad AMR exome AF: 0.000182

Gnomad ASJ exome AF: 0.0136

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000140

Gnomad OTH exome AF: 0.00101

GnomAD4 exome AF: 0.000334 AC: 475 AN: 1420642 Hom.: 1 Cov.: 35 AF XY: 0.000336 AC XY: 237 AN XY: 704412

African (AFR) AF: 0.00 AC: 0 AN: 31860

American (AMR) AF: 0.000389 AC: 15 AN: 38550

Ashkenazi Jewish (ASJ) AF: 0.0140 AC: 345 AN: 24728

East Asian (EAS) AF: 0.00 AC: 0 AN: 38864

South Asian (SAS) AF: 0.0000128 AC: 1 AN: 78370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51648

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5628

European-Non Finnish (NFE) AF: 0.0000586 AC: 64 AN: 1092424

Other (OTH) AF: 0.000854 AC: 50 AN: 58570

GnomAD4 genome AF: 0.000336 AC: 51 AN: 151894 Hom.: 0 Cov.: 31 AF XY: 0.000324 AC XY: 24 AN XY: 74174

African (AFR) AF: 0.00 AC: 0 AN: 41372

American (AMR) AF: 0.0000657 AC: 1 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 43 AN: 3466

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67912

Other (OTH) AF: 0.00192 AC: 4 AN: 2080

Alfa AF: 0.000776 Hom.: 2

Bravo AF: 0.000431

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000266 AC: 1

ESP6500EA AF: 0.000486 AC: 4

ExAC AF: 0.000399 AC: 48

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	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	0.10
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.9
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.18
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.33	T
Polyphen		0.64	P
Vest4		0.17
MVP		0.49
ClinPred		0.022	T
GERP RS		5.1
Varity_R		0.16
gMVP		0.022
Mutation Taster		=3/97	disease causing

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: rs201021891; hg19: chr6-123869623;