rs181287533

chr6-123548606-G-Achr6-123548606-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_006073.4(TRDN):c.239C>T(p.Ser80Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000585 in 1,401,120 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000047 (1 hom.)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 5.76

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 -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.010376781).
• BP6: Variant 6-123548606-G-A is Benign according to our data. Variant chr6-123548606-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 449704.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00016 (23/143748) while in subpopulation AMR AF= 0.00139 (20/14366). AF 95% confidence interval is 0.000922. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRDN	NM_006073.4	c.239C>T	p.Ser80Phe	missense_variant	3/41	ENST00000334268.9
LOC105377982	XR_001743833.2	n.2346-4750G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRDN	ENST00000334268.9	c.239C>T	p.Ser80Phe	missense_variant	3/41	1	NM_006073.4	A2
	ENST00000648704.1	n.449-4816G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000160 AC: 23 AN: 143642 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000535

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00139

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: 0.00

Gnomad OTH AF: 0.000517

GnomAD3 exomes AF: 0.000404 AC: 35 AN: 86694 Hom.: 1 AF XY: 0.000253 AC XY: 12 AN XY: 47370

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00753

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000541

GnomAD4 exome AF: 0.0000469 AC: 59 AN: 1257372 Hom.: 1 Cov.: 35 AF XY: 0.0000357 AC XY: 22 AN XY: 615930

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00350

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000782

GnomAD4 genome AF: 0.000160 AC: 23 AN: 143748 Hom.: 0 Cov.: 31 AF XY: 0.000215 AC XY: 15 AN XY: 69738

Gnomad4 AFR AF: 0.0000534

Gnomad4 AMR AF: 0.00139

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000511

Bravo AF: 0.000359

ExAC AF: 0.000520 AC: 58

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 08, 2017

The S80F variant has not been published as pathogenic or been reported as benign to our knowledge. The S80F variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. The Exome Aggregation Consortium reports S80F was observed in 13/1,450 (0.9%) alleles from individuals of Latino background, including one homozygous individual (Lek et al., 2016). -

Catecholaminergic polymorphic ventricular tachycardia 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

TRDN NM_006073.3 exon 3 p. Ser80Phe (c.239C>T): This variant has not been reported in the literature and is present in 0.66% (35/5298) of Latino alleles in the Genome Aggregation Database, including one homozygote (http://gnomad.broadinstitute.org/variant/6-123869751-G-A). This variant is present in ClinVar (Variation ID:449704). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

TRDN-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 26, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2023

This alteration is classified as likely 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	Pathogenic	0.79
BayesDel_addAF	Benign	0.0094	T
BayesDel_noAF	Pathogenic	0.25
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T;.;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.010	T;T;T;T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Uncertain	2.6	M;M;.;M
MutationTaster	Benign	0.98	D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.9	D;.;D;D
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.71
MVP		0.77
ClinPred		0.23	T
GERP RS		5.3
Varity_R		0.55
gMVP		0.42

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: rs181287533; hg19: chr6-123869751;