rs148596612

Positions:

• chr6-123516182-CCTTTTT-C

Variant summary

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

The NM_006073.4(TRDN):​c.503_508del​(p.Glu168_Lys169del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,486,878 control chromosomes in the GnomAD database, including 74 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (24 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (50 hom.)
• Consequence: TRDN NM_006073.4 inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.98

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 6-123516182-CCTTTTT-C is Benign according to our data. Variant chr6-123516182-CCTTTTT-C is described in ClinVar as [Benign]. Clinvar id is 227122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-123516182-CCTTTTT-C is described in Lovd as [Benign]. Variant chr6-123516182-CCTTTTT-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0846 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRDN	NM_006073.4	c.503_508del	p.Glu168_Lys169del	inframe_deletion	6/41	ENST00000334268.9	NP_006064.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9	c.503_508del	p.Glu168_Lys169del	inframe_deletion	6/41	1	NM_006073.4	ENSP00000333984	A2

Frequencies

GnomAD3 genomes AF: 0.00342 AC: 520 AN: 151844 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000986

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0916

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00449 AC: 648 AN: 144416 Hom.: 22 AF XY: 0.00421 AC XY: 323 AN XY: 76692

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000890

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0644

Gnomad SAS exome AF: 0.00100

Gnomad FIN exome AF: 0.0000605

Gnomad NFE exome AF: 0.0000906

Gnomad OTH exome AF: 0.00341

GnomAD4 exome AF: 0.00106 AC: 1413 AN: 1334916 Hom.: 50 AF XY: 0.00109 AC XY: 710 AN XY: 654006

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000128

Gnomad4 ASJ exome AF: 0.0000429

Gnomad4 EAS exome AF: 0.0321

Gnomad4 SAS exome AF: 0.00173

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000376

Gnomad4 OTH exome AF: 0.00342

GnomAD4 genome AF: 0.00341 AC: 518 AN: 151962 Hom.: 24 Cov.: 32 AF XY: 0.00393 AC XY: 292 AN XY: 74254

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000985

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0914

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000883

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.000720 Hom.: 1

Bravo AF: 0.00397

Asia WGS AF: 0.0390 AC: 134 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	Jun 09, 2015	p.Glu168_Lys169del in exon 6 of TRDN: This variant is not expected to have clini cal significance because it has been identified in 9% (49/536) of East Asian chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs148596612). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

TRDN-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 09, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

-

- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 01, 2016

This alteration is classified as 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. -

Catecholaminergic polymorphic ventricular tachycardia 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs148596612; hg19: chr6-123837327;