chr6-123337680-G-T

Position:

• chr6-123337680-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006073.4(TRDN):​c.1370-11C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 1,409,608 control chromosomes in the GnomAD database, including 30,454 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3551 hom., cov: 32)
  • Exomes 𝑓: 0.18 (26903 hom.)
• Consequence: TRDN NM_006073.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.002238
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.950

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]

LOC105377984 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 6-123337680-G-T is Benign according to our data. Variant chr6-123337680-G-T is described in ClinVar as [Benign]. Clinvar id is 227111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-123337680-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.612 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRDN	NM_006073.4	c.1370-11C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000334268.9
LOC105377984	XR_942947.3	n.262G>T		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRDN	ENST00000334268.9	c.1370-11C>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_006073.4	A2

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28076 AN: 151812 Hom.: 3550 Cov.: 32

Gnomad AFR AF: 0.0845

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.194

Gnomad EAS AF: 0.630

Gnomad SAS AF: 0.412

Gnomad FIN AF: 0.275

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.171

GnomAD3 exomes AF: 0.249 AC: 32103 AN: 129056 Hom.: 5123 AF XY: 0.256 AC XY: 17534 AN XY: 68620

Gnomad AFR exome AF: 0.0807

Gnomad AMR exome AF: 0.278

Gnomad ASJ exome AF: 0.200

Gnomad EAS exome AF: 0.607

Gnomad SAS exome AF: 0.381

Gnomad FIN exome AF: 0.270

Gnomad NFE exome AF: 0.168

Gnomad OTH exome AF: 0.215

GnomAD4 exome AF: 0.177 AC: 222199 AN: 1257678 Hom.: 26903 Cov.: 21 AF XY: 0.183 AC XY: 114115 AN XY: 622224

Gnomad4 AFR exome AF: 0.0678

Gnomad4 AMR exome AF: 0.263

Gnomad4 ASJ exome AF: 0.184

Gnomad4 EAS exome AF: 0.657

Gnomad4 SAS exome AF: 0.366

Gnomad4 FIN exome AF: 0.245

Gnomad4 NFE exome AF: 0.145

Gnomad4 OTH exome AF: 0.179

GnomAD4 genome AF: 0.185 AC: 28091 AN: 151930 Hom.: 3551 Cov.: 32 AF XY: 0.198 AC XY: 14671 AN XY: 74246

Gnomad4 AFR AF: 0.0847

Gnomad4 AMR AF: 0.215

Gnomad4 ASJ AF: 0.194

Gnomad4 EAS AF: 0.630

Gnomad4 SAS AF: 0.413

Gnomad4 FIN AF: 0.275

Gnomad4 NFE AF: 0.176

Gnomad4 OTH AF: 0.168

Alfa AF: 0.136 Hom.: 375

Bravo AF: 0.174

Asia WGS AF: 0.411 AC: 1420 AN: 3464

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	1370-11C>A in intron 21 of TRDN: This variant is not expected to have clinical s ignificance because it has been identified in 15.0% (794/5284) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs9401658). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Catecholaminergic polymorphic ventricular tachycardia 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	10
DANN	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0022
dbscSNV1_RF	Benign	0.21
SpliceAI score (max)		0.13		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: rs9401658; hg19: chr6-123658825;