rs77768246

Positions:

chr6-123439007-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The ENST00000334268.9(TRDN):c.932-4C>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 0.00144 in 1,544,922 control chromosomes in the GnomAD database, including 52 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 0.0016 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 45 hom. )

Consequence

TRDN
ENST00000334268.9 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.001468

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.268

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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 6-123439007-G-C is Benign according to our data. Variant chr6-123439007-G-C is described in ClinVar as [Benign]. Clinvar id is 227124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-123439007-G-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00155 (236/152010) while in subpopulation EAS AF= 0.0412 (213/5164). AF 95% confidence interval is 0.0367. There are 7 homozygotes in gnomad4. There are 132 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
TRDN	NM_006073.4 linkuse as main transcript	c.932-4C>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	ENST00000334268.9	NP_006064.2
TRDN	NM_001251987.2 linkuse as main transcript	c.932-4C>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		NP_001238916.1
TRDN	NM_001407315.1 linkuse as main transcript	c.872-4C>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		NP_001394244.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9 linkuse as main transcript	c.932-4C>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	1	NM_006073.4	ENSP00000333984	A2	Q13061-1
TRDN-AS1	ENST00000587106.6 linkuse as main transcript	n.572-596G>C	intron_variant, non_coding_transcript_variant	5
TRDN	ENST00000662930.1 linkuse as main transcript	c.932-4C>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			ENSP00000499585

Frequencies

GnomAD3 genomes

AF:

0.00156

AC:

237

AN:

151892

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0413

Gnomad SAS

AF:

0.00187

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00298

AC:

479

AN:

160620

Hom.:

AF XY:

0.00276

AC XY:

234

AN XY:

84698

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0368

Gnomad SAS exome

AF:

0.00132

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000768

Gnomad OTH exome

AF:

0.00229

GnomAD4 exome

AF:

0.00143

AC:

1991

AN:

1392912

Hom.:

Cov.:

AF XY:

0.00141

AC XY:

972

AN XY:

687974

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000403

Gnomad4 EAS exome

AF:

0.0460

Gnomad4 SAS exome

AF:

0.00149

Gnomad4 FIN exome

AF:

0.0000203

Gnomad4 NFE exome

AF:

0.0000400

Gnomad4 OTH exome

AF:

0.00218

GnomAD4 genome

AF:

0.00155

AC:

236

AN:

152010

Hom.:

Cov.:

AF XY:

0.00178

AC XY:

132

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0412

Gnomad4 SAS

AF:

0.00187

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000291

Hom.:

Bravo

AF:

0.00181

Asia WGS

AF:

0.0260

AC:

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	932-4C>G in intron 10 of TRDN: This variant is not expected to have clinical sig nificance because it is not located within the conserved splice consensus sequen ce. It has been identified in 5.6% (10/178) of Japanese chromosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.gov/projects/SN P; dbSNP rs77768246). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2017	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. -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

8.9

DANN

Benign

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0015

dbscSNV1_RF

Benign

0.15

SpliceAI score (max)

0.060

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