6-123393619-C-T

Position:

chr6-123393619-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006073.4(TRDN):c.1105+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0436 in 1,599,324 control chromosomes in the GnomAD database, including 1,732 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.032 ( 122 hom., cov: 32)

Exomes 𝑓: 0.045 ( 1610 hom. )

Consequence

TRDN
NM_006073.4 splice_donor_5th_base, intron

Scores

Splicing: ADA: 0.4824

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.0620

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:

TRDN-AS1 (HGNC:40592): (TRDN antisense RNA 1)

TRDN-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 6-123393619-C-T is Benign according to our data. Variant chr6-123393619-C-T is described in ClinVar as [Benign]. Clinvar id is 227105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-123393619-C-T is described in Lovd as [Benign].

BA1

GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.052 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
TRDN	NM_006073.4 linkuse as main transcript	c.1105+5G>A	splice_donor_5th_base_variant, intron_variant	ENST00000334268.9	NP_006064.2
TRDN	NM_001251987.2 linkuse as main transcript	c.1108+5G>A	splice_donor_5th_base_variant, intron_variant		NP_001238916.1
TRDN	NM_001407315.1 linkuse as main transcript	c.1048+5G>A	splice_donor_5th_base_variant, intron_variant		NP_001394244.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9 linkuse as main transcript	c.1105+5G>A	splice_donor_5th_base_variant, intron_variant	1	NM_006073.4	ENSP00000333984	A2	Q13061-1
TRDN-AS1	ENST00000587106.6 linkuse as main transcript	n.55+4144C>T	intron_variant, non_coding_transcript_variant	5
TRDN	ENST00000662930.1 linkuse as main transcript	c.1108+5G>A	splice_donor_5th_base_variant, intron_variant			ENSP00000499585

Frequencies

GnomAD3 genomes

AF:

0.0320

AC:

4860

AN:

151918

Hom.:

122

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00967

Gnomad AMI

AF:

0.0658

Gnomad AMR

AF:

0.0269

Gnomad ASJ

AF:

0.0208

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00850

Gnomad FIN

AF:

0.0290

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0512

Gnomad OTH

AF:

0.0354

GnomAD3 exomes

AF:

0.0317

AC:

7284

AN:

229690

Hom.:

149

AF XY:

0.0320

AC XY:

3980

AN XY:

124248

show subpopulations

Gnomad AFR exome

AF:

0.00666

Gnomad AMR exome

AF:

0.0226

Gnomad ASJ exome

AF:

0.0198

Gnomad EAS exome

AF:

0.000117

Gnomad SAS exome

AF:

0.0110

Gnomad FIN exome

AF:

0.0315

Gnomad NFE exome

AF:

0.0499

Gnomad OTH exome

AF:

0.0374

GnomAD4 exome

AF:

0.0448

AC:

64862

AN:

1447288

Hom.:

1610

Cov.:

AF XY:

0.0438

AC XY:

31493

AN XY:

718744

show subpopulations

Gnomad4 AFR exome

AF:

0.00724

Gnomad4 AMR exome

AF:

0.0250

Gnomad4 ASJ exome

AF:

0.0197

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0118

Gnomad4 FIN exome

AF:

0.0320

Gnomad4 NFE exome

AF:

0.0524

Gnomad4 OTH exome

AF:

0.0391

GnomAD4 genome

AF:

0.0320

AC:

4862

AN:

152036

Hom.:

122

Cov.:

AF XY:

0.0295

AC XY:

2190

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00967

Gnomad4 AMR

AF:

0.0269

Gnomad4 ASJ

AF:

0.0208

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00850

Gnomad4 FIN

AF:

0.0290

Gnomad4 NFE

AF:

0.0512

Gnomad4 OTH

AF:

0.0350

Alfa

AF:

0.0455

Hom.:

236

Bravo

AF:

0.0316

Asia WGS

AF:

0.00779

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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	Nov 24, 2014	1105+5G>A in intron 13 of TRDN: This variant is not expected to have clinical si gnificance because it has been identified in 4.8% (393/8134) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs41284430). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.48

dbscSNV1_RF

Benign

0.51

SpliceAI score (max)

0.48

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.48

Position offset: 5

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