6-123269870-T-C

Position:

chr6-123269870-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006073.4(TRDN):c.1721-4A>G 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 0.00085 in 1,610,318 control chromosomes in the GnomAD database, including 14 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 0.0043 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00049 ( 10 hom. )

Consequence

TRDN
NM_006073.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00007607

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.13

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:

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=-0.52).

BP6

Variant 6-123269870-T-C is Benign according to our data. Variant chr6-123269870-T-C is described in ClinVar as [Benign]. Clinvar id is 227116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00427 (649/152050) while in subpopulation AFR AF= 0.0146 (605/41524). AF 95% confidence interval is 0.0136. There are 4 homozygotes in gnomad4. There are 306 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRDN	NM_006073.4 linkuse as main transcript	c.1721-4A>G		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 linkuse as main transcript	c.1721-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006073.4	A2	Q13061-1

Frequencies

GnomAD3 genomes

AF:

0.00427

AC:

648

AN:

151932

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0146

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00210

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00106

AC:

260

AN:

246202

Hom.:

AF XY:

0.000906

AC XY:

121

AN XY:

133576

show subpopulations

Gnomad AFR exome

AF:

0.0136

Gnomad AMR exome

AF:

0.000824

Gnomad ASJ exome

AF:

0.000300

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000331

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000108

Gnomad OTH exome

AF:

0.00135

GnomAD4 exome

AF:

0.000494

AC:

720

AN:

1458268

Hom.:

Cov.:

AF XY:

0.000449

AC XY:

326

AN XY:

725274

show subpopulations

Gnomad4 AFR exome

AF:

0.0148

Gnomad4 AMR exome

AF:

0.000901

Gnomad4 ASJ exome

AF:

0.000269

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000700

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000414

Gnomad4 OTH exome

AF:

0.00176

GnomAD4 genome

AF:

0.00427

AC:

649

AN:

152050

Hom.:

Cov.:

AF XY:

0.00412

AC XY:

306

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.0146

Gnomad4 AMR

AF:

0.00210

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000501

Hom.:

Bravo

AF:

0.00437

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000180

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	TRDN: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2018	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. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	1721-4A>G in intron 30 of TRDN: This variant is not expected to have clinical si gnificance because it is not located within the conserved splice consensus seque nce. It has been identified in 1.2% (44/3766) of African American chromosomes fr om a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washi ngton.edu/EVS; dbSNP rs60743141). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 11, 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

-0.52

CADD

Benign

DANN

Benign

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000076

dbscSNV1_RF

Benign

0.0040

SpliceAI score (max)

0.070

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