rs79182520

Variant names:

• chr6-123530560-G-A
• rs79182520
• NM_006073.4:c.430C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-123530560-G-A
• chr6-123530560-G-T

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.430C>T​(p.His144Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00225 in 1,240,332 control chromosomes in the GnomAD database, including 103 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H144R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0034 (23 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (80 hom.)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.75
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015872121).
• BP6: Variant 6-123530560-G-A is Benign according to our data. Variant chr6-123530560-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0847 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.430C>T	p.His144Tyr	missense	Exon 5 of 41	NP_006064.2	Q13061-1
	TRDN	NM_001251987.2		c.430C>T	p.His144Tyr	missense	Exon 5 of 21	NP_001238916.1	A0A590UJV0
	TRDN	NM_001407315.1		c.430C>T	p.His144Tyr	missense	Exon 5 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.430C>T	p.His144Tyr	missense	Exon 5 of 41	ENSP00000333984.5	Q13061-1
	TRDN	ENST00000628709.2	TSL:1	c.430C>T	p.His144Tyr	missense	Exon 5 of 9	ENSP00000486095.1	Q13061-2
	TRDN	ENST00000546248.6	TSL:1	c.430C>T	p.His144Tyr	missense	Exon 5 of 8	ENSP00000439281.2	H9ME53

Frequencies

GnomAD3 genomes AF: 0.00345 AC: 523 AN: 151532 Hom.: 23 Cov.: 33

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000920

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0917

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000737

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.00391 AC: 343 AN: 87800 AF XY: 0.00355

Gnomad AFR exome AF: 0.000271

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0704

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000813

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00209 AC: 2275 AN: 1088676 Hom.: 80 Cov.: 19 AF XY: 0.00204 AC XY: 1098 AN XY: 537104

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000182 AC: 4 AN: 21994

American (AMR) AF: 0.0000645 AC: 1 AN: 15510

Ashkenazi Jewish (ASJ) AF: 0.0000512 AC: 1 AN: 19516

East Asian (EAS) AF: 0.0731 AC: 1966 AN: 26888

South Asian (SAS) AF: 0.00196 AC: 114 AN: 58114

European-Finnish (FIN) AF: 0.0000255 AC: 1 AN: 39272

Middle Eastern (MID) AF: 0.000531 AC: 2 AN: 3770

European-Non Finnish (NFE) AF: 0.0000442 AC: 38 AN: 858956

Other (OTH) AF: 0.00331 AC: 148 AN: 44656

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00344 AC: 521 AN: 151656 Hom.: 23 Cov.: 33 AF XY: 0.00393 AC XY: 291 AN XY: 74092

African (AFR) AF: 0.000217 AC: 9 AN: 41416

American (AMR) AF: 0.000919 AC: 14 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.0916 AC: 471 AN: 5144

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.0000738 AC: 5 AN: 67790

Other (OTH) AF: 0.00285 AC: 6 AN: 2106

Alfa AF: 0.000472 Hom.: 1

Bravo AF: 0.00409

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00334 AC: 76

Asia WGS AF: 0.0390 AC: 132 AN: 3414

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1 (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 5 (1)
-	-	1	not provided (1)
-	-	1	TRDN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.0097
Eigen_PC	Benign	0.067
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.8
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.14
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.024	D
Polyphen		0.91	P
Vest4		0.15
MVP		0.47
ClinPred		0.023	T
GERP RS		5.2
PromoterAI		-0.0020	Neutral
Varity_R		0.16
gMVP		0.037
Mutation Taster		=95/5	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: rs79182520; hg19: chr6-123851705; COSMIC: COSV62115204;