rs55704802

Positions:

• chr6-123278360-A-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_006073.4(TRDN):​c.1538-13T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00746 in 1,272,424 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0076 (43 hom.)
• Consequence: TRDN NM_006073.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.745

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 6-123278360-A-C is Benign according to our data. Variant chr6-123278360-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 227113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-123278360-A-C is described in Lovd as [Benign]. Variant chr6-123278360-A-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00634 (965/152232) while in subpopulation NFE AF= 0.00995 (677/68012). AF 95% confidence interval is 0.00933. There are 6 homozygotes in gnomad4. There are 453 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRDN	NM_006073.4	c.1538-13T>G		intron_variant		ENST00000334268.9	NP_006064.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9	c.1538-13T>G		intron_variant		1	NM_006073.4	ENSP00000333984.5

Frequencies

GnomAD3 genomes AF: 0.00634 AC: 965 AN: 152114 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00754

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00995

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00648 AC: 749 AN: 115502 Hom.: 4 AF XY: 0.00602 AC XY: 370 AN XY: 61476

Gnomad AFR exome AF: 0.000893

Gnomad AMR exome AF: 0.00382

Gnomad ASJ exome AF: 0.0188

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000453

Gnomad FIN exome AF: 0.00123

Gnomad NFE exome AF: 0.0108

Gnomad OTH exome AF: 0.00644

GnomAD4 exome AF: 0.00761 AC: 8526 AN: 1120192 Hom.: 43 Cov.: 18 AF XY: 0.00750 AC XY: 4148 AN XY: 552836

Gnomad4 AFR exome AF: 0.000995

Gnomad4 AMR exome AF: 0.00430

Gnomad4 ASJ exome AF: 0.0171

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000401

Gnomad4 FIN exome AF: 0.00120

Gnomad4 NFE exome AF: 0.00877

Gnomad4 OTH exome AF: 0.00683

GnomAD4 genome AF: 0.00634 AC: 965 AN: 152232 Hom.: 6 Cov.: 33 AF XY: 0.00608 AC XY: 453 AN XY: 74450

Gnomad4 AFR AF: 0.00180

Gnomad4 AMR AF: 0.00753

Gnomad4 ASJ AF: 0.0176

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00995

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00881 Hom.: 4

Bravo AF: 0.00664

Asia WGS AF: 0.000870 AC: 3 AN: 3462

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	TRDN: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 18, 2015	c.1538-13T>G in intron 25 of TRDN: This variant is not expected to have clinical significance because it has been identified in 1.6% (130/8168) of European chro mosomes including 1 homozygous individual by the Exome Aggregation Consortium(ht tp://exac.broadinstitute.org/; dbSNP rs55704802). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2023	- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Catecholaminergic polymorphic ventricular tachycardia 5 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.6
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: -1
DS_AL_spliceai		0.32		Position offset: -13

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs55704802; hg19: chr6-123599505;