rs370788759

chr6-123548568-G-Achr6-123548568-G-Cchr6-123548568-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.277C>T(p.Arg93Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,554,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R93S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000070 (0 hom.)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.89

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=0.010916054).
• BP6: Variant 6-123548568-G-A is Benign according to our data. Variant chr6-123548568-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 415187.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000552 (83/150464) while in subpopulation AFR AF= 0.00193 (79/40928). AF 95% confidence interval is 0.00159. There are 0 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRDN	NM_006073.4	c.277C>T	p.Arg93Cys	missense_variant	3/41	ENST00000334268.9
LOC105377982	XR_001743833.2	n.2346-4788G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRDN	ENST00000334268.9	c.277C>T	p.Arg93Cys	missense_variant	3/41	1	NM_006073.4	A2
	ENST00000648704.1	n.449-4854G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 83 AN: 150352 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000664

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: 0.0000148

Gnomad OTH AF: 0.000966

GnomAD3 exomes AF: 0.000187 AC: 35 AN: 186764 Hom.: 0 AF XY: 0.000169 AC XY: 17 AN XY: 100436

Gnomad AFR exome AF: 0.00244

Gnomad AMR exome AF: 0.000119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000172

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000705 AC: 99 AN: 1404404 Hom.: 0 Cov.: 35 AF XY: 0.0000619 AC XY: 43 AN XY: 695198

Gnomad4 AFR exome AF: 0.00176

Gnomad4 AMR exome AF: 0.0000800

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000533

Gnomad4 SAS exome AF: 0.0000782

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000259

Gnomad4 OTH exome AF: 0.0000518

GnomAD4 genome AF: 0.000552 AC: 83 AN: 150464 Hom.: 0 Cov.: 31 AF XY: 0.000546 AC XY: 40 AN XY: 73292

Gnomad4 AFR AF: 0.00193

Gnomad4 AMR AF: 0.0000663

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.000957

Alfa AF: 0.000182 Hom.: 0

Bravo AF: 0.000502

ESP6500AA AF: 0.00136 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000234 AC: 28

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 22, 2022

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 21, 2020

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	Benign	0.26
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.17	T;.;.;.
Eigen	Benign	-0.039
Eigen_PC	Benign	0.043
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.83	T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N;.;N
MutationTaster	Benign	0.95	N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.9	N;.;N;N
REVEL	Benign	0.073
Sift	Uncertain	0.0030	D;.;D;D
Sift4G	Uncertain	0.018	D;D;D;D
Polyphen		0.94	P;.;.;.
Vest4		0.18
MVP		0.34
ClinPred		0.036	T
GERP RS		3.3
Varity_R		0.19
gMVP		0.082

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs370788759; hg19: chr6-123869713; COSMIC: COSV100521887;