6-123548462-G-C

Position:

• chr6-123548462-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006073.4(TRDN):​c.383C>G​(p.Thr128Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.508 in 1,556,642 control chromosomes in the GnomAD database, including 207,684 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T128T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.50 (19905 hom., cov: 30)
  • Exomes 𝑓: 0.51 (187779 hom.)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0810

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.3423745E-5).
• BP6: Variant 6-123548462-G-C is Benign according to our data. Variant chr6-123548462-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 227119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-123548462-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.533 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRDN	NM_006073.4	c.383C>G	p.Thr128Ser	missense_variant	3/41	ENST00000334268.9
LOC105377982	XR_001743833.2	n.2346-4894G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRDN	ENST00000334268.9	c.383C>G	p.Thr128Ser	missense_variant	3/41	1	NM_006073.4	A2
	ENST00000648704.1	n.449-4960G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.503 AC: 76085 AN: 151308 Hom.: 19898 Cov.: 30

Gnomad AFR AF: 0.539

Gnomad AMI AF: 0.453

Gnomad AMR AF: 0.387

Gnomad ASJ AF: 0.580

Gnomad EAS AF: 0.0824

Gnomad SAS AF: 0.392

Gnomad FIN AF: 0.583

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.531

Gnomad OTH AF: 0.507

GnomAD3 exomes AF: 0.442 AC: 86427 AN: 195600 Hom.: 21274 AF XY: 0.448 AC XY: 47411 AN XY: 105842

Gnomad AFR exome AF: 0.531

Gnomad AMR exome AF: 0.250

Gnomad ASJ exome AF: 0.578

Gnomad EAS exome AF: 0.0792

Gnomad SAS exome AF: 0.390

Gnomad FIN exome AF: 0.571

Gnomad NFE exome AF: 0.517

Gnomad OTH exome AF: 0.481

GnomAD4 exome AF: 0.509 AC: 715045 AN: 1405216 Hom.: 187779 Cov.: 33 AF XY: 0.507 AC XY: 352821 AN XY: 696268

Gnomad4 AFR exome AF: 0.543

Gnomad4 AMR exome AF: 0.278

Gnomad4 ASJ exome AF: 0.583

Gnomad4 EAS exome AF: 0.109

Gnomad4 SAS exome AF: 0.397

Gnomad4 FIN exome AF: 0.573

Gnomad4 NFE exome AF: 0.534

Gnomad4 OTH exome AF: 0.497

GnomAD4 genome AF: 0.503 AC: 76121 AN: 151426 Hom.: 19905 Cov.: 30 AF XY: 0.497 AC XY: 36810 AN XY: 73990

Gnomad4 AFR AF: 0.539

Gnomad4 AMR AF: 0.386

Gnomad4 ASJ AF: 0.580

Gnomad4 EAS AF: 0.0820

Gnomad4 SAS AF: 0.393

Gnomad4 FIN AF: 0.583

Gnomad4 NFE AF: 0.531

Gnomad4 OTH AF: 0.507

Alfa AF: 0.507 Hom.: 14156

Bravo AF: 0.487

TwinsUK AF: 0.537 AC: 1990

ALSPAC AF: 0.529 AC: 2040

ESP6500AA AF: 0.549 AC: 2066

ESP6500EA AF: 0.537 AC: 4418

ExAC AF: 0.422 AC: 50234

Asia WGS AF: 0.267 AC: 931 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Thr128Ser in exon 3 of TRDN: This variant is not expected to have clinical signi ficance because it has been identified in 46.3% (3802/8220) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs9490809). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

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
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.98
DANN	Benign	0.24
DEOGEN2	Benign	0.17	T;.;.;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.45	T;T;T;T
MetaRNN	Benign	0.000023	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	M;M;.;M
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.66	N;.;N;N
REVEL	Benign	0.043
Sift	Benign	0.43	T;.;T;T
Sift4G	Benign	0.33	T;T;T;T
Polyphen		0.058	B;.;.;.
Vest4		0.031
MutPred		0.32		Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);
ClinPred		0.0053	T
GERP RS		2.0
Varity_R		0.034
gMVP		0.011

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs9490809; hg19: chr6-123869607;