rs181571822

Variant names:

• chr6-123255878-C-T
• rs181571822
• NM_006073.4:c.1895G>A
• TRDN p.Arg632Lys

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_006073.4(TRDN):​c.1895G>A​(p.Arg632Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000717 in 1,352,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 0.319
• Publications: 2 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: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• catecholaminergic polymorphic ventricular tachycardia 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0066376626).
• BP6: Variant 6-123255878-C-T is Benign according to our data. Variant chr6-123255878-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 426462.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000407 (62/152158) while in subpopulation AFR AF = 0.00123 (51/41530). AF 95% confidence interval is 0.000959. There are 0 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006073.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRDN	NM_006073.4	MANE Select	c.1895G>A	p.Arg632Lys	missense	Exon 36 of 41	NP_006064.2	Q13061-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRDN	ENST00000334268.9	TSL:1 MANE Select	c.1895G>A	p.Arg632Lys	missense	Exon 36 of 41	ENSP00000333984.5	Q13061-1
	TRDN	ENST00000962661.1		c.1898G>A	p.Arg633Lys	missense	Exon 36 of 41	ENSP00000632720.1
	TRDN	ENST00000962654.1		c.1895G>A	p.Arg632Lys	missense	Exon 36 of 41	ENSP00000632713.1

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152040 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

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: 0.00

GnomAD2 exomes AF: 0.0000697 AC: 5 AN: 71720 AF XY: 0.0000251

Gnomad AFR exome AF: 0.00139

Gnomad AMR exome AF: 0.000287

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 AF: 0.0000292 AC: 35 AN: 1200638 Hom.: 0 Cov.: 23 AF XY: 0.0000254 AC XY: 15 AN XY: 589612

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

African (AFR) AF: 0.00117 AC: 27 AN: 23164

American (AMR) AF: 0.000159 AC: 2 AN: 12594

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18810

East Asian (EAS) AF: 0.00 AC: 0 AN: 27926

South Asian (SAS) AF: 0.00 AC: 0 AN: 52174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43864

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3624

European-Non Finnish (NFE) AF: 0.00000103 AC: 1 AN: 969798

Other (OTH) AF: 0.000103 AC: 5 AN: 48684

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000968998), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000407 AC: 62 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74400

African (AFR) AF: 0.00123 AC: 51 AN: 41530

American (AMR) AF: 0.000720 AC: 11 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67974

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000452 Hom.: 0

Bravo AF: 0.000631

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)
-	1	-	Catecholaminergic polymorphic ventricular tachycardia 1 (1)
-	1	-	Catecholaminergic polymorphic ventricular tachycardia 5 (1)
-	1	-	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.3
DANN	Benign	0.39
DEOGEN2	Benign	0.065	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.00016	N
LIST_S2	Benign	0.20	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.55	N
PhyloP100		0.32
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.31	N
REVEL	Benign	0.011
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Varity_R		0.038
gMVP		0.015
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs181571822;

hg19: chr6-123577023;