NM_006073.4:c.1871-15G>A

Variant names:

• chr6-123255917-C-T
• rs59935057
• NM_006073.4:c.1871-15G>A

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.1871-15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00321 in 1,264,438 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (27 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (79 hom.)
• Consequence: TRDN NM_006073.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.187
• Publications: 3 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: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• 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 (BayesDel_noAF=-0.99).
• BP6: Variant 6-123255917-C-T is Benign according to our data. Variant chr6-123255917-C-T is described in ClinVar as Benign. ClinVar VariationId is 227117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0735 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.1871-15G>A		intron	N/A	NP_006064.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRDN	ENST00000334268.9	TSL:1 MANE Select	c.1871-15G>A		intron	N/A	ENSP00000333984.5
	TRDN	ENST00000962661.1		c.1874-15G>A		intron	N/A	ENSP00000632720.1
	TRDN	ENST00000962654.1		c.1871-15G>A		intron	N/A	ENSP00000632713.1

Frequencies

GnomAD3 genomes AF: 0.00822 AC: 1249 AN: 151970 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0172

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00270

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0802

Gnomad SAS AF: 0.0104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00266 AC: 146 AN: 54960 AF XY: 0.00272

Gnomad AFR exome AF: 0.0152

Gnomad AMR exome AF: 0.00108

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00524

GnomAD4 exome AF: 0.00250 AC: 2786 AN: 1112352 Hom.: 79 Cov.: 20 AF XY: 0.00245 AC XY: 1323 AN XY: 539638

African (AFR) AF: 0.0175 AC: 387 AN: 22092

American (AMR) AF: 0.00148 AC: 15 AN: 10154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16426

East Asian (EAS) AF: 0.0689 AC: 1805 AN: 26210

South Asian (SAS) AF: 0.00771 AC: 284 AN: 36814

European-Finnish (FIN) AF: 0.0000250 AC: 1 AN: 39950

Middle Eastern (MID) AF: 0.00160 AC: 5 AN: 3120

European-Non Finnish (NFE) AF: 0.0000383 AC: 35 AN: 912784

Other (OTH) AF: 0.00567 AC: 254 AN: 44802

GnomAD4 genome AF: 0.00834 AC: 1268 AN: 152086 Hom.: 27 Cov.: 32 AF XY: 0.00893 AC XY: 664 AN XY: 74332

African (AFR) AF: 0.0177 AC: 735 AN: 41510

American (AMR) AF: 0.00269 AC: 41 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0799 AC: 413 AN: 5172

South Asian (SAS) AF: 0.0104 AC: 50 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67998

Other (OTH) AF: 0.00993 AC: 21 AN: 2114

Alfa AF: 0.00506 Hom.: 2

Bravo AF: 0.00921

Asia WGS AF: 0.0480 AC: 166 AN: 3470

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	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
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.14
DANN	Benign	0.14
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs59935057; hg19: chr6-123577062; COSMIC: COSV62116198;