6-123316457-C-T

Variant names:

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.1510G>A(p.Gly504Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000481 in 1,609,974 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/26 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G504G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 2 hom. )

Consequence

TRDN
NM_006073.4 missense, splice_region

Scores

Splicing: ADA: 0.7097

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.12

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:

LOC124901393 (HGNC:):

LOC124901393 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=0.0076751113).

BP6

Variant 6-123316457-C-T is Benign according to our data. Variant chr6-123316457-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 415181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00273 (414/151844) while in subpopulation AFR AF = 0.00955 (396/41468). AF 95% confidence interval is 0.00877. There are 0 homozygotes in GnomAd4. There are 197 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRDN	NM_006073.4	MANE Select	c.1510G>A	p.Gly504Ser	missense splice_region	Exon 24 of 41	NP_006064.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TRDN	ENST00000334268.9	TSL:1 MANE Select	c.1510G>A	p.Gly504Ser	missense splice_region	Exon 24 of 41	ENSP00000333984.5
TRDN	ENST00000962661.1		c.1513G>A	p.Gly505Ser	missense splice_region	Exon 24 of 41	ENSP00000632720.1
TRDN	ENST00000962654.1		c.1510G>A	p.Gly504Ser	missense splice_region	Exon 24 of 41	ENSP00000632713.1

Frequencies

GnomAD3 genomes

AF:

0.00272

AC:

413

AN:

151726

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00955

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000594

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:

0.0000147

Gnomad OTH

AF:

0.00384

GnomAD2 exomes

AF:

0.000586

AC:

145

AN:

247396

AF XY:

0.000365

show subpopulations

Gnomad AFR exome

AF:

0.00827

Gnomad AMR exome

AF:

0.000409

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000893

Gnomad OTH exome

AF:

0.000500

GnomAD4 exome

AF:

0.000247

AC:

360

AN:

1458130

Hom.:

Cov.:

AF XY:

0.000237

AC XY:

172

AN XY:

725440

show subpopulations

African (AFR)

AF:

0.00793

AC:

264

AN:

33296

American (AMR)

AF:

0.000539

AC:

AN:

44496

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25990

East Asian (EAS)

AF:

0.00

AC:

AN:

39470

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86128

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53304

Middle Eastern (MID)

AF:

0.000523

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

1109550

Other (OTH)

AF:

0.000781

AC:

AN:

60160

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

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:

0.00273

AC:

414

AN:

151844

Hom.:

Cov.:

AF XY:

0.00265

AC XY:

197

AN XY:

74202

show subpopulations

African (AFR)

AF:

0.00955

AC:

396

AN:

41468

American (AMR)

AF:

0.000593

AC:

AN:

15182

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67846

Other (OTH)

AF:

0.00380

AC:

AN:

2104

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:

0.000917

Hom.:

Bravo

AF:

0.00303

ESP6500AA

AF:

0.00739

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000605

AC:

Asia WGS

AF:

0.000868

AC:

AN:

3470

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Cardiovascular phenotype (1)

Catecholaminergic polymorphic ventricular tachycardia 1 (1)

TRDN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.62

CADD

Uncertain

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.080

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.59

M_CAP

Benign

0.0088

MetaRNN

Benign

0.0077

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.55

PhyloP100

1.1

PrimateAI

Benign

0.41

PROVEAN

Benign

0.21

REVEL

Benign

0.021

Sift

Uncertain

0.029

Sift4G

Benign

0.76

Polyphen

0.014

Vest4

0.30

MVP

0.048

ClinPred

0.022

GERP RS

1.9

Varity_R

0.066

gMVP

0.0034

Mutation Taster

=78/22

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.71

dbscSNV1_RF

Benign

0.68

SpliceAI score (max)

0.75

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.75

Position offset: 0

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