chr6-123269870-T-C

Variant names:

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

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.1721-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00085 in 1,610,318 control chromosomes in the GnomAD database, including 14 homozygotes. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (10 hom.)
• Consequence: TRDN NM_006073.4 splice_region, intron
• Scores: Splicing: ADA: 0.00007607
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 6-123269870-T-C is Benign according to our data. Variant chr6-123269870-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227116.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 = 0.00427 (649/152050) while in subpopulation AFR AF = 0.0146 (605/41524). AF 95% confidence interval is 0.0136. There are 4 homozygotes in GnomAd4. There are 306 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.1721-4A>G		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>G		splice_region intron	N/A	ENSP00000333984.5	Q13061-1
	TRDN	ENST00000962661.1		c.1724-4A>G		splice_region intron	N/A	ENSP00000632720.1
	TRDN	ENST00000962654.1		c.1721-4A>G		splice_region intron	N/A	ENSP00000632713.1

Frequencies

GnomAD3 genomes AF: 0.00427 AC: 648 AN: 151932 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

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: 0.000103

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00106 AC: 260 AN: 246202 AF XY: 0.000906

Gnomad AFR exome AF: 0.0136

Gnomad AMR exome AF: 0.000824

Gnomad ASJ exome AF: 0.000300

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000108

Gnomad OTH exome AF: 0.00135

GnomAD4 exome AF: 0.000494 AC: 720 AN: 1458268 Hom.: 10 Cov.: 30 AF XY: 0.000449 AC XY: 326 AN XY: 725274

African (AFR) AF: 0.0148 AC: 495 AN: 33362

American (AMR) AF: 0.000901 AC: 40 AN: 44390

Ashkenazi Jewish (ASJ) AF: 0.000269 AC: 7 AN: 26048

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

South Asian (SAS) AF: 0.0000700 AC: 6 AN: 85770

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

Middle Eastern (MID) AF: 0.00348 AC: 20 AN: 5748

European-Non Finnish (NFE) AF: 0.0000414 AC: 46 AN: 1110040

Other (OTH) AF: 0.00176 AC: 106 AN: 60192

GnomAD4 genome AF: 0.00427 AC: 649 AN: 152050 Hom.: 4 Cov.: 32 AF XY: 0.00412 AC XY: 306 AN XY: 74328

African (AFR) AF: 0.0146 AC: 605 AN: 41524

American (AMR) AF: 0.00210 AC: 32 AN: 15232

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

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

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67886

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00103 Hom.: 1

Bravo AF: 0.00437

Asia WGS AF: 0.00231 AC: 9 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000180

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	10
DANN	Benign	0.78
PhyloP100		1.1
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000076
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.070		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;