rs6901953

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_006073.4(TRDN):c.1188A>G(p.Lys396Lys) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 1,470,594 control chromosomes in the GnomAD database, including 95,898 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 Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 9543 hom., cov: 32)

Exomes 𝑓: 0.35 ( 86355 hom. )

Consequence

TRDN
NM_006073.4 splice_region, synonymous

Scores

Splicing: ADA: 0.002327

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.10

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 6-123377897-T-C is Benign according to our data. Variant chr6-123377897-T-C is described in ClinVar as [Benign]. Clinvar id is 227106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-123377897-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.1 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.398 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRDN	NM_006073.4 linkuse as main transcript	c.1188A>G	p.Lys396Lys	splice_region_variant, synonymous_variant	17/41	ENST00000334268.9	NP_006064.2	Q13061-1
TRDN	NM_001251987.2 linkuse as main transcript	c.1191A>G	p.Lys397Lys	splice_region_variant, synonymous_variant	17/21		NP_001238916.1	A0A590UJV0Q8IVK2
TRDN	NM_001407315.1 linkuse as main transcript	c.1131A>G	p.Lys377Lys	splice_region_variant, synonymous_variant	16/20		NP_001394244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9 linkuse as main transcript	c.1188A>G	p.Lys396Lys	splice_region_variant, synonymous_variant	17/41	1	NM_006073.4	ENSP00000333984.5		Q13061-1
TRDN	ENST00000662930.1 linkuse as main transcript	c.1191A>G	p.Lys397Lys	splice_region_variant, synonymous_variant	17/21			ENSP00000499585.1		A0A590UJV0

Frequencies

GnomAD3 genomes

AF:

0.346

AC:

52611

AN:

151980

Hom.:

9526

Cov.:

show subpopulations

Gnomad AFR

AF:

0.338

Gnomad AMI

AF:

0.271

Gnomad AMR

AF:

0.406

Gnomad ASJ

AF:

0.401

Gnomad EAS

AF:

0.115

Gnomad SAS

AF:

0.161

Gnomad FIN

AF:

0.265

Gnomad MID

AF:

0.427

Gnomad NFE

AF:

0.378

Gnomad OTH

AF:

0.387

GnomAD3 exomes

AF:

0.333

AC:

52080

AN:

156336

Hom.:

9330

AF XY:

0.323

AC XY:

26813

AN XY:

82984

show subpopulations

Gnomad AFR exome

AF:

0.345

Gnomad AMR exome

AF:

0.414

Gnomad ASJ exome

AF:

0.394

Gnomad EAS exome

AF:

0.119

Gnomad SAS exome

AF:

0.182

Gnomad FIN exome

AF:

0.289

Gnomad NFE exome

AF:

0.389

Gnomad OTH exome

AF:

0.378

GnomAD4 exome

AF:

0.355

AC:

467949

AN:

1318496

Hom.:

86355

Cov.:

AF XY:

0.349

AC XY:

228237

AN XY:

654760

show subpopulations

Gnomad4 AFR exome

AF:

0.340

Gnomad4 AMR exome

AF:

0.411

Gnomad4 ASJ exome

AF:

0.395

Gnomad4 EAS exome

AF:

0.140

Gnomad4 SAS exome

AF:

0.176

Gnomad4 FIN exome

AF:

0.287

Gnomad4 NFE exome

AF:

0.377

Gnomad4 OTH exome

AF:

0.349

GnomAD4 genome

AF:

0.346

AC:

52661

AN:

152098

Hom.:

9543

Cov.:

AF XY:

0.336

AC XY:

24970

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.337

Gnomad4 AMR

AF:

0.406

Gnomad4 ASJ

AF:

0.401

Gnomad4 EAS

AF:

0.115

Gnomad4 SAS

AF:

0.161

Gnomad4 FIN

AF:

0.265

Gnomad4 NFE

AF:

0.378

Gnomad4 OTH

AF:

0.390

Alfa

AF:

0.377

Hom.:

21608

Bravo

AF:

0.361

Asia WGS

AF:

0.192

AC:

670

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Lys396Lys in exon 17 of TRDN: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 36.4% (2890/7950) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs6901953). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 2015

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

Genome-Nilou Lab

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0023

dbscSNV1_RF

Benign

0.13

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over