rs6569336

Positions:

• chr6-123337631-G-T

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.1408C>A​(p.Leu470Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,422,180 control chromosomes in the GnomAD database, including 3,068 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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. L470L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.085 (1786 hom., cov: 32)
  • Exomes 𝑓: 0.010 (1282 hom.)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0770

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]

LOC105377984 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048668683).
• BP6: Variant 6-123337631-G-T is Benign according to our data. Variant chr6-123337631-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 227112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-123337631-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRDN	NM_006073.4	c.1408C>A	p.Leu470Met	missense_variant	22/41	ENST00000334268.9
LOC105377984	XR_942947.3	n.214-1G>T		splice_acceptor_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRDN	ENST00000334268.9	c.1408C>A	p.Leu470Met	missense_variant	22/41	1	NM_006073.4	A2

Frequencies

GnomAD3 genomes AF: 0.0851 AC: 12923 AN: 151898 Hom.: 1783 Cov.: 32

Gnomad AFR AF: 0.289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0303

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.0639

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00118

Gnomad OTH AF: 0.0628

GnomAD3 exomes AF: 0.0247 AC: 3225 AN: 130400 Hom.: 313 AF XY: 0.0240 AC XY: 1662 AN XY: 69254

Gnomad AFR exome AF: 0.275

Gnomad AMR exome AF: 0.0128

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00121

Gnomad SAS exome AF: 0.0575

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00145

Gnomad OTH exome AF: 0.0121

GnomAD4 exome AF: 0.0105 AC: 13318 AN: 1270164 Hom.: 1282 Cov.: 20 AF XY: 0.0112 AC XY: 7009 AN XY: 628308

Gnomad4 AFR exome AF: 0.277

Gnomad4 AMR exome AF: 0.0154

Gnomad4 ASJ exome AF: 0.000216

Gnomad4 EAS exome AF: 0.000686

Gnomad4 SAS exome AF: 0.0577

Gnomad4 FIN exome AF: 0.0000215

Gnomad4 NFE exome AF: 0.000556

Gnomad4 OTH exome AF: 0.0216

GnomAD4 genome AF: 0.0852 AC: 12946 AN: 152016 Hom.: 1786 Cov.: 32 AF XY: 0.0821 AC XY: 6103 AN XY: 74326

Gnomad4 AFR AF: 0.288

Gnomad4 AMR AF: 0.0302

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0639

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00118

Gnomad4 OTH AF: 0.0621

Alfa AF: 0.0110 Hom.: 294

Bravo AF: 0.0954

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.252 AC: 572

ESP6500EA AF: 0.000800 AC: 4

ExAC AF: 0.0460 AC: 1142

Asia WGS AF: 0.0480 AC: 167 AN: 3470

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Leu470Met in exon 22 of TRDN: This variant is not expected to have clinical sign ificance because it has been identified in 25.2% (572/2268) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs6569336). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 08, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 20, 2023	- -
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. -

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

Jul 15, 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
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.021
Sift	Uncertain	0.019	D
Sift4G	Benign	0.15	T
Polyphen		0.61	P
Vest4		0.064
ClinPred		0.0031	T
GERP RS		0.78
Varity_R		0.082
gMVP		0.0093

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs6569336; hg19: chr6-123658776;