6-123260632-G-T

Variant names:

• chr6-123260632-G-T
• rs763939252
• NM_006073.4:c.1811C>A

Variant summary

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

The NM_006073.4(TRDN):​c.1811C>A​(p.Thr604Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T604I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000010 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000024 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.864
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRDN	NM_006073.4	c.1811C>A	p.Thr604Lys	missense_variant	Exon 34 of 41	ENST00000334268.9	NP_006064.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9	c.1811C>A	p.Thr604Lys	missense_variant	Exon 34 of 41	1	NM_006073.4	ENSP00000333984.5

Frequencies

GnomAD3 genomes AF: 0.0000103 AC: 1 AN: 96794 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000114 AC: 1 AN: 87748 AF XY: 0.0000210

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000240 AC: 25 AN: 1042790 Hom.: 0 Cov.: 23 AF XY: 0.0000194 AC XY: 10 AN XY: 515620

⚠️ 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: 21352

American (AMR) AF: 0.000117 AC: 2 AN: 17120

Ashkenazi Jewish (ASJ) AF: 0.000112 AC: 2 AN: 17844

East Asian (EAS) AF: 0.00 AC: 0 AN: 26210

South Asian (SAS) AF: 0.0000533 AC: 3 AN: 56266

European-Finnish (FIN) AF: 0.0000533 AC: 2 AN: 37500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3182

European-Non Finnish (NFE) AF: 0.0000170 AC: 14 AN: 821340

Other (OTH) AF: 0.0000476 AC: 2 AN: 41976

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0000103 AC: 1 AN: 96810 Hom.: 0 Cov.: 28 AF XY: 0.0000222 AC XY: 1 AN XY: 45040

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

African (AFR) AF: 0.00 AC: 0 AN: 22718

American (AMR) AF: 0.00 AC: 0 AN: 7228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2694

East Asian (EAS) AF: 0.00 AC: 0 AN: 3322

South Asian (SAS) AF: 0.00 AC: 0 AN: 2510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3960

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 110

European-Non Finnish (NFE) AF: 0.0000191 AC: 1 AN: 52334

Other (OTH) AF: 0.00 AC: 0 AN: 1170

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.000460 AC: 11

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	14
DANN	Benign	0.51
DEOGEN2	Benign	0.078	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.20	N
PhyloP100		0.86
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.019
Sift	Benign	0.27	T
Sift4G	Benign	1.0	T
Polyphen		0.0050	B
Vest4		0.19
MVP		0.014
ClinPred		0.035	T
GERP RS		2.0
Varity_R		0.060
gMVP		0.029
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.21		Position offset: 6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs763939252; hg19: chr6-123581777;