Genetic Variant TRDN:p.Glu168Lys (chr6-123516189-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006073.4(TRDN):c.502G>A(p.Glu168Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000233 in 1,482,694 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E168A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 6 hom. )

Consequence

TRDN
NM_006073.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.03

Publications

1 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008609533).

BP6

Variant 6-123516189-C-T is Benign according to our data. Variant chr6-123516189-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 240287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000113 (17/150752) while in subpopulation SAS AF = 0.00335 (16/4776). AF 95% confidence interval is 0.0021. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 6 AD,AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TRDN	NM_006073.4	MANE Select	c.502G>A	p.Glu168Lys	missense	Exon 6 of 41	NP_006064.2
TRDN	NM_001251987.2		c.502G>A	p.Glu168Lys	missense	Exon 6 of 21	NP_001238916.1
TRDN	NM_001407315.1		c.502G>A	p.Glu168Lys	missense	Exon 6 of 20	NP_001394244.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TRDN	ENST00000334268.9	TSL:1 MANE Select	c.502G>A	p.Glu168Lys	missense	Exon 6 of 41	ENSP00000333984.5
TRDN	ENST00000628709.2	TSL:1	c.502G>A	p.Glu168Lys	missense	Exon 6 of 9	ENSP00000486095.1
TRDN	ENST00000546248.6	TSL:1	c.502G>A	p.Glu168Lys	missense	Exon 6 of 8	ENSP00000439281.2

Frequencies

GnomAD3 genomes

AF:

0.000113

AC:

AN:

150632

Hom.:

Cov.:

show subpopulations

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:

0.00335

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000504

AC:

AN:

140800

AF XY:

0.000696

show subpopulations

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:

0.0000609

Gnomad NFE exome

AF:

0.0000183

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000247

AC:

329

AN:

1331942

Hom.:

Cov.:

AF XY:

0.000368

AC XY:

240

AN XY:

652548

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:

29710

American (AMR)

AF:

0.00

AC:

AN:

30912

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23188

East Asian (EAS)

AF:

0.00

AC:

AN:

32738

South Asian (SAS)

AF:

0.00412

AC:

309

AN:

74952

European-Finnish (FIN)

AF:

0.000114

AC:

AN:

43802

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5262

European-Non Finnish (NFE)

AF:

0.00000386

AC:

AN:

1037078

Other (OTH)

AF:

0.000203

AC:

AN:

54300

⚠️ 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: 0.373

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000113

AC:

AN:

150752

Hom.:

Cov.:

AF XY:

0.000177

AC XY:

AN XY:

73562

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41428

American (AMR)

AF:

0.00

AC:

AN:

15188

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

4272

South Asian (SAS)

AF:

0.00335

AC:

AN:

4776

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10494

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67824

Other (OTH)

AF:

0.00

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.437

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000154

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.00182

AC:

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Catecholaminergic polymorphic ventricular tachycardia 1 (1)

Catecholaminergic polymorphic ventricular tachycardia 1;C3809536:Catecholaminergic polymorphic ventricular tachycardia 5 (1)

not provided (1)

TRDN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.042

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

Eigen

Benign

0.072

Eigen_PC

Benign

0.088

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.78

M_CAP

Pathogenic

0.46

MetaRNN

Benign

0.0086

MetaSVM

Benign

-0.72

MutationAssessor

Benign

1.9

PhyloP100

3.0

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.75

REVEL

Benign

0.12

Sift

Uncertain

0.019

Sift4G

Benign

0.36

Polyphen

0.67

Vest4

0.16

MVP

0.47

ClinPred

0.076

GERP RS

3.8

PromoterAI

-0.020

Neutral

(source)

Varity_R

0.14

gMVP

0.0031

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over