dbSNP rs777796676: TRDN:p.Lys192Arg (chr6-123512338-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006073.4(TRDN):c.575A>G(p.Lys192Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000738 in 1,354,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K192T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

TRDN
NM_006073.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.71

Publications

0 publications found

Variant links:

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

TRDN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.10202068).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRDN	NM_006073.4 link	c.575A>G	p.Lys192Arg	missense_variant	Exon 7 of 41	ENST00000334268.9	NP_006064.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9 link	c.575A>G	p.Lys192Arg	missense_variant	Exon 7 of 41	1	NM_006073.4	ENSP00000333984.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.38e-7

AC:

AN:

1354232

Hom.:

Cov.:

AF XY:

0.00000148

AC XY:

AN XY:

673572

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

31380

American (AMR)

AF:

0.00

AC:

AN:

39208

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24800

East Asian (EAS)

AF:

0.00

AC:

AN:

38042

South Asian (SAS)

AF:

0.0000127

AC:

AN:

78556

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50666

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5492

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1029866

Other (OTH)

AF:

0.00

AC:

AN:

56222

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

T;.;.

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.74

T;T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.10

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;L;.

PhyloP100

2.7

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.65

N;.;N

REVEL

Benign

0.020

Sift

Benign

0.14

T;.;D

Sift4G

Benign

0.24

T;T;T

Polyphen

0.035

B;.;.

Vest4

0.15

MutPred

0.41

Loss of methylation at K192 (P = 0.0022);Loss of methylation at K192 (P = 0.0022);Loss of methylation at K192 (P = 0.0022);

MVP

0.22

ClinPred

0.50

GERP RS

3.7

Varity_R

0.075

gMVP

0.0031

Mutation Taster

=90/10

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over