6-123218604-C-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_006073.4(TRDN):c.2187G>T(p.Gln729His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000453 in 1,611,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q729E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

TRDN
NM_006073.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -1.52

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: 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=0.03874451).

BP6

Variant 6-123218604-C-A is Benign according to our data. Variant chr6-123218604-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 839610.

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.2187G>T	p.Gln729His	missense	Exon 41 of 41	NP_006064.2	Q13061-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRDN	ENST00000334268.9	TSL:1 MANE Select	c.2187G>T	p.Gln729His	missense	Exon 41 of 41	ENSP00000333984.5	Q13061-1
TRDN	ENST00000962661.1		c.2190G>T	p.Gln730His	missense	Exon 41 of 41	ENSP00000632720.1
TRDN	ENST00000962654.1		c.2187G>T	p.Gln729His	missense	Exon 41 of 41	ENSP00000632713.1

Frequencies

GnomAD3 genomes

AF:

0.000224

AC:

AN:

151902

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000797

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000658

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:

0.0000688

AC:

AN:

247146

AF XY:

0.0000448

show subpopulations

Gnomad AFR exome

AF:

0.00104

Gnomad AMR exome

AF:

0.0000293

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:

0.0000267

AC:

AN:

1459140

Hom.:

Cov.:

AF XY:

0.0000331

AC XY:

AN XY:

725882

show subpopulations

African (AFR)

AF:

0.000931

AC:

AN:

33290

American (AMR)

AF:

0.0000225

AC:

AN:

44458

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25962

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.00

AC:

AN:

86112

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53304

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110408

Other (OTH)

AF:

0.000116

AC:

AN:

60196

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.000224

AC:

AN:

151902

Hom.:

Cov.:

AF XY:

0.000270

AC XY:

AN XY:

74150

show subpopulations

African (AFR)

AF:

0.000797

AC:

AN:

41416

American (AMR)

AF:

0.0000658

AC:

AN:

15208

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67912

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

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:

0.000198

Hom.:

Bravo

AF:

0.000264

ESP6500AA

AF:

0.00106

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000745

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cardiovascular phenotype (1)

Catecholaminergic polymorphic ventricular tachycardia 1 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.51

CADD

Benign

9.4

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.071

LIST_S2

Benign

0.51

M_CAP

Benign

0.014

MetaRNN

Benign

0.039

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

PhyloP100

-1.5

PrimateAI

Benign

0.37

REVEL

Benign

0.12

Sift4G

Pathogenic

0.0

Polyphen

0.77

Vest4

0.13

MutPred

0.15

Gain of catalytic residue at Q729 (P = 0.1607)

MVP

0.072

ClinPred

0.057

GERP RS

-1.8

Varity_R

0.16

gMVP

0.16

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over