chr6-123377892-T-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_006073.4(TRDN):c.1193A>T(p.Glu398Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000071 in 1,507,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

TRDN
NM_006073.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 3.14

Publications

2 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: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
catecholaminergic polymorphic ventricular tachycardia 5
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, 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

TRDN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.030006707).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000394 (60/152294) while in subpopulation AFR AF = 0.00144 (60/41580). AF 95% confidence interval is 0.00115. 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. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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	UniProt
TRDN	NM_006073.4	MANE Select	c.1193A>T	p.Glu398Val	missense	Exon 17 of 41	NP_006064.2	Q13061-1
TRDN	NM_001251987.2		c.1196A>T	p.Glu399Val	missense	Exon 17 of 21	NP_001238916.1	A0A590UJV0
TRDN	NM_001407315.1		c.1136A>T	p.Glu379Val	missense	Exon 16 of 20	NP_001394244.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRDN	ENST00000334268.9	TSL:1 MANE Select	c.1193A>T	p.Glu398Val	missense	Exon 17 of 41	ENSP00000333984.5	Q13061-1
TRDN	ENST00000962661.1		c.1196A>T	p.Glu399Val	missense	Exon 17 of 41	ENSP00000632720.1
TRDN	ENST00000962654.1		c.1193A>T	p.Glu398Val	missense	Exon 17 of 41	ENSP00000632713.1

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00145

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000111

AC:

AN:

162328

AF XY:

0.000104

show subpopulations

Gnomad AFR exome

AF:

0.00200

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

AF:

0.0000347

AC:

AN:

1355362

Hom.:

Cov.:

AF XY:

0.0000327

AC XY:

AN XY:

672148

show subpopulations

African (AFR)

AF:

0.00145

AC:

AN:

30304

American (AMR)

AF:

0.00

AC:

AN:

35798

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24826

East Asian (EAS)

AF:

0.00

AC:

AN:

36242

South Asian (SAS)

AF:

0.00

AC:

AN:

78100

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49074

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4520

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1039976

Other (OTH)

AF:

0.0000531

AC:

AN:

56522

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000394

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00144

AC:

AN:

41580

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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:

0.000214

Hom.:

Bravo

AF:

0.000400

ESP6500AA

AF:

0.00171

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000733

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Cardiovascular phenotype (1)

Catecholaminergic polymorphic ventricular tachycardia 1 (1)

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

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.51

M_CAP

Benign

0.030

MetaRNN

Benign

0.030

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

PhyloP100

3.1

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-2.2

REVEL

Benign

0.12

Sift

Pathogenic

0.0

Sift4G

Benign

0.068

Polyphen

1.0

Vest4

0.28

MVP

0.41

ClinPred

0.20

GERP RS

5.1

Varity_R

0.29

gMVP

0.036

Mutation Taster

=71/29

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

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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