6-123273365-TA-TAA

Variant names:

• chr6-123273365-T-TA
• rs147062785
• NM_006073.4:c.1598-3dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_006073.4(TRDN):​c.1598-3dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.164 in 960,706 control chromosomes in the GnomAD database, including 16,167 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3143 hom., cov: 28)
  • Exomes 𝑓: 0.16 (13024 hom.)
• Consequence: TRDN NM_006073.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0890
• Publications: 5 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 -16 ACMG points.

• BP6: Variant 6-123273365-T-TA is Benign according to our data. Variant chr6-123273365-T-TA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.522 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.1598-3dupT		splice_region intron	N/A	NP_006064.2	Q13061-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRDN	ENST00000334268.9	TSL:1 MANE Select	c.1598-3_1598-2insT		splice_region intron	N/A	ENSP00000333984.5	Q13061-1
	TRDN	ENST00000962661.1		c.1601-3_1601-2insT		splice_region intron	N/A	ENSP00000632720.1
	TRDN	ENST00000962654.1		c.1598-3_1598-2insT		splice_region intron	N/A	ENSP00000632713.1

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27549 AN: 151638 Hom.: 3144 Cov.: 28

Gnomad AFR AF: 0.0972

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.182

Gnomad ASJ AF: 0.195

Gnomad EAS AF: 0.539

Gnomad SAS AF: 0.347

Gnomad FIN AF: 0.300

Gnomad MID AF: 0.213

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.169

GnomAD2 exomes AF: 0.226 AC: 17011 AN: 75230 AF XY: 0.231

Gnomad AFR exome AF: 0.0848

Gnomad AMR exome AF: 0.175

Gnomad ASJ exome AF: 0.198

Gnomad EAS exome AF: 0.495

Gnomad FIN exome AF: 0.294

Gnomad NFE exome AF: 0.164

Gnomad OTH exome AF: 0.200

GnomAD4 exome AF: 0.160 AC: 129762 AN: 808952 Hom.: 13024 Cov.: 11 AF XY: 0.167 AC XY: 68058 AN XY: 406406

African (AFR) AF: 0.0702 AC: 1092 AN: 15550

American (AMR) AF: 0.167 AC: 1641 AN: 9804

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 2736 AN: 15946

East Asian (EAS) AF: 0.449 AC: 5792 AN: 12914

South Asian (SAS) AF: 0.303 AC: 15293 AN: 50470

European-Finnish (FIN) AF: 0.266 AC: 8018 AN: 30108

Middle Eastern (MID) AF: 0.213 AC: 843 AN: 3950

European-Non Finnish (NFE) AF: 0.140 AC: 88879 AN: 636318

Other (OTH) AF: 0.161 AC: 5468 AN: 33892

GnomAD4 genome AF: 0.182 AC: 27577 AN: 151754 Hom.: 3143 Cov.: 28 AF XY: 0.193 AC XY: 14316 AN XY: 74128

African (AFR) AF: 0.0975 AC: 4046 AN: 41500

American (AMR) AF: 0.182 AC: 2769 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 676 AN: 3468

East Asian (EAS) AF: 0.539 AC: 2770 AN: 5138

South Asian (SAS) AF: 0.348 AC: 1679 AN: 4822

European-Finnish (FIN) AF: 0.300 AC: 3144 AN: 10494

Middle Eastern (MID) AF: 0.226 AC: 66 AN: 292

European-Non Finnish (NFE) AF: 0.176 AC: 11954 AN: 67840

Other (OTH) AF: 0.167 AC: 350 AN: 2096

Alfa AF: 0.171 Hom.: 513

Bravo AF: 0.167

Asia WGS AF: 0.353 AC: 1200 AN: 3414

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.089
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs147062785; hg19: chr6-123594510; COSMIC: COSV62134492;