6-123393633-C-T

Variant names:

• chr6-123393633-C-T
• rs35047281
• NM_006073.4:c.1096G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006073.4(TRDN):​c.1096G>A​(p.Ala366Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00206 in 1,604,516 control chromosomes in the GnomAD database, including 71 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A366A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.012 (34 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (37 hom.)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.232
• Publications: 8 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-AS1 (HGNC:40592): (TRDN antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032596886).
• BP6: Variant 6-123393633-C-T is Benign according to our data. Variant chr6-123393633-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0115 (1754/152010) while in subpopulation AFR AF = 0.0397 (1647/41482). AF 95% confidence interval is 0.0381. There are 34 homozygotes in GnomAd4. There are 840 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 AD,AR gene

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.1096G>A	p.Ala366Thr	missense	Exon 13 of 41	NP_006064.2	Q13061-1
	TRDN	NM_001251987.2		c.1099G>A	p.Ala367Thr	missense	Exon 13 of 21	NP_001238916.1	A0A590UJV0
	TRDN	NM_001407315.1		c.1039G>A	p.Ala347Thr	missense	Exon 12 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.1096G>A	p.Ala366Thr	missense	Exon 13 of 41	ENSP00000333984.5	Q13061-1
	TRDN	ENST00000962661.1		c.1099G>A	p.Ala367Thr	missense	Exon 13 of 41	ENSP00000632720.1
	TRDN	ENST00000962654.1		c.1099G>A	p.Ala367Thr	missense	Exon 13 of 41	ENSP00000632713.1

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1754 AN: 151896 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.0398

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00485

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00257 AC: 606 AN: 236116 AF XY: 0.00207

Gnomad AFR exome AF: 0.0382

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000567

Gnomad OTH exome AF: 0.00104

GnomAD4 exome AF: 0.00107 AC: 1553 AN: 1452506 Hom.: 37 Cov.: 30 AF XY: 0.000937 AC XY: 676 AN XY: 721798

African (AFR) AF: 0.0389 AC: 1295 AN: 33260

American (AMR) AF: 0.00164 AC: 72 AN: 43790

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25794

East Asian (EAS) AF: 0.00 AC: 0 AN: 39568

South Asian (SAS) AF: 0.0000589 AC: 5 AN: 84844

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52786

Middle Eastern (MID) AF: 0.000696 AC: 4 AN: 5744

European-Non Finnish (NFE) AF: 0.0000316 AC: 35 AN: 1106788

Other (OTH) AF: 0.00237 AC: 142 AN: 59932

GnomAD4 genome AF: 0.0115 AC: 1754 AN: 152010 Hom.: 34 Cov.: 32 AF XY: 0.0113 AC XY: 840 AN XY: 74298

African (AFR) AF: 0.0397 AC: 1647 AN: 41482

American (AMR) AF: 0.00485 AC: 74 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000417 AC: 2 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67940

Other (OTH) AF: 0.0133 AC: 28 AN: 2110

Alfa AF: 0.00436 Hom.: 22

Bravo AF: 0.0125

ESP6500AA AF: 0.0370 AC: 133

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.00315 AC: 380

Asia WGS AF: 0.00433 AC: 15 AN: 3478

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.48
DANN	Benign	0.56
DEOGEN2	Benign	0.070	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.20	N
PhyloP100		-0.23
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.020
Sift	Benign	0.88	T
Sift4G	Benign	0.65	T
Polyphen		0.0010	B
Vest4		0.14
MVP		0.014
ClinPred		0.0011	T
GERP RS		0.88
Varity_R		0.030
gMVP		0.0089
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35047281; hg19: chr6-123714778; COSMIC: COSV107392932;