6-123269870-T-A

Variant names:

• chr6-123269870-T-A
• rs60743141
• NM_006073.4:c.1721-4A>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_006073.4(TRDN):​c.1721-4A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000422 in 1,610,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: TRDN NM_006073.4 splice_region, intron
• Scores: Splicing: ADA: 0.001448
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.13
• Publications: 2 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 6-123269870-T-A is Benign according to our data. Variant chr6-123269870-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1040678.

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.1721-4A>T		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.1721-4A>T		splice_region intron	N/A	ENSP00000333984.5	Q13061-1
	TRDN	ENST00000962661.1		c.1724-4A>T		splice_region intron	N/A	ENSP00000632720.1
	TRDN	ENST00000962654.1		c.1721-4A>T		splice_region intron	N/A	ENSP00000632713.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151932 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

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: 0.00

GnomAD2 exomes AF: 0.00000406 AC: 1 AN: 246202 AF XY: 0.00000749

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000896

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000439 AC: 64 AN: 1458292 Hom.: 0 Cov.: 30 AF XY: 0.0000469 AC XY: 34 AN XY: 725286

African (AFR) AF: 0.00 AC: 0 AN: 33374

American (AMR) AF: 0.00 AC: 0 AN: 44392

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39446

South Asian (SAS) AF: 0.00 AC: 0 AN: 85770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53272

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.0000577 AC: 64 AN: 1110042

Other (OTH) AF: 0.00 AC: 0 AN: 60198

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151932 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74200

African (AFR) AF: 0.0000242 AC: 1 AN: 41402

American (AMR) AF: 0.00 AC: 0 AN: 15212

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67894

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.0000340

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	9.6
DANN	Benign	0.75
PhyloP100		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0014
dbscSNV1_RF	Benign	0.030
SpliceAI score (max)		0.19		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: rs60743141; hg19: chr6-123591015;