6-123273365-TA-TAA

Position:

• chr6-123273365-TA-TAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_006073.4(TRDN):​c.1598-3_1598-2insT variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0890

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 6-123273365-T-TA is Benign according to our data. Variant chr6-123273365-T-TA is described in ClinVar as [Likely_benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRDN	NM_006073.4	c.1598-3_1598-2insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000334268.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRDN	ENST00000334268.9	c.1598-3_1598-2insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006073.4	A2

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

GnomAD3 exomes AF: 0.226 AC: 17011 AN: 75230 Hom.: 2358 AF XY: 0.231 AC XY: 9670 AN XY: 41894

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 SAS exome AF: 0.314

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

Gnomad4 AFR exome AF: 0.0702

Gnomad4 AMR exome AF: 0.167

Gnomad4 ASJ exome AF: 0.172

Gnomad4 EAS exome AF: 0.449

Gnomad4 SAS exome AF: 0.303

Gnomad4 FIN exome AF: 0.266

Gnomad4 NFE exome AF: 0.140

Gnomad4 OTH exome AF: 0.161

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

Gnomad4 AFR AF: 0.0975

Gnomad4 AMR AF: 0.182

Gnomad4 ASJ AF: 0.195

Gnomad4 EAS AF: 0.539

Gnomad4 SAS AF: 0.348

Gnomad4 FIN AF: 0.300

Gnomad4 NFE AF: 0.176

Gnomad4 OTH AF: 0.167

Alfa AF: 0.171 Hom.: 513

Bravo AF: 0.167

Asia WGS AF: 0.353 AC: 1200 AN: 3414

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 26, 2014	c.1598-3_1598-2insT in intron 27 of TRDN: This variant is not expected to have c linical significance because it has been identified in 16% (764/4822) of Europea n American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.wash ington.edu/EVS/; dbSNP rs147062785). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 09, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2018	- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 15, 2015

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs147062785; hg19: chr6-123594510;