rs573190326

Variant names:

• chr6-123278322-C-A
• rs573190326
• NM_006073.4:c.1563G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-123278322-C-A
• chr6-123278322-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006073.4(TRDN):​c.1563G>T​(p.Lys521Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000176 in 1,139,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K521K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.86
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• catecholaminergic polymorphic ventricular tachycardia 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• familial long QT syndrome

  Inheritance: AR Classification: STRONG Submitted by: G2P
• long QT syndrome

  Inheritance: AR Classification: STRONG Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08463192).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRDN	NM_006073.4	c.1563G>T	p.Lys521Asn	missense_variant	Exon 26 of 41	ENST00000334268.9	NP_006064.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9	c.1563G>T	p.Lys521Asn	missense_variant	Exon 26 of 41	1	NM_006073.4	ENSP00000333984.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000176 AC: 2 AN: 1139368 Hom.: 0 Cov.: 20 AF XY: 0.00000178 AC XY: 1 AN XY: 561240

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24034

American (AMR) AF: 0.0000492 AC: 1 AN: 20310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20858

East Asian (EAS) AF: 0.00 AC: 0 AN: 28470

South Asian (SAS) AF: 0.00 AC: 0 AN: 65224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38674

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4900

European-Non Finnish (NFE) AF: 0.00000112 AC: 1 AN: 889920

Other (OTH) AF: 0.00 AC: 0 AN: 46978

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	13
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.90	L
PhyloP100		-1.9
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.031
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.071	T
Polyphen		0.80	P
Vest4		0.15
MutPred		0.36		Loss of methylation at K521 (P = 0.0039);
MVP		0.055
ClinPred		0.45	T
GERP RS		-3.4
Varity_R		0.20
gMVP		0.0081
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs573190326; hg19: chr6-123599467;