dbSNP rs200243235: TRDN:p.Gln456Arg (chr6-123352541-T-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_006073.4(TRDN):c.1367A>G(p.Gln456Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 1,611,392 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. Q456P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 5 hom. )

Consequence

TRDN
NM_006073.4 missense, splice_region

Scores

Splicing: ADA: 0.8442

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:7

Conservation

PhyloP100: 2.96

Publications

4 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013671964).

BP6

Variant 6-123352541-T-C is Benign according to our data. Variant chr6-123352541-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 229345.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00129 (196/152054) while in subpopulation NFE AF = 0.00239 (162/67862). AF 95% confidence interval is 0.00209. There are 0 homozygotes in GnomAd4. There are 87 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 5 AR,AD 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	UniProt
TRDN	NM_006073.4	MANE Select	c.1367A>G	p.Gln456Arg	missense splice_region	Exon 21 of 41	NP_006064.2	Q13061-1
TRDN	NM_001251987.2		c.1370A>G	p.Gln457Arg	missense	Exon 21 of 21	NP_001238916.1	A0A590UJV0
TRDN	NM_001407315.1		c.1310A>G	p.Gln437Arg	missense	Exon 20 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.1367A>G	p.Gln456Arg	missense splice_region	Exon 21 of 41	ENSP00000333984.5	Q13061-1
TRDN	ENST00000662930.1		c.1370A>G	p.Gln457Arg	missense	Exon 21 of 21	ENSP00000499585.1	A0A590UJV0
TRDN	ENST00000962661.1		c.1370A>G	p.Gln457Arg	missense splice_region	Exon 21 of 41	ENSP00000632720.1

Frequencies

GnomAD3 genomes

AF:

0.00129

AC:

196

AN:

151936

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00239

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00119

AC:

294

AN:

247280

AF XY:

0.00128

show subpopulations

Gnomad AFR exome

AF:

0.00104

Gnomad AMR exome

AF:

0.0000586

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000233

Gnomad NFE exome

AF:

0.00194

Gnomad OTH exome

AF:

0.00151

GnomAD4 exome

AF:

0.00209

AC:

3051

AN:

1459338

Hom.:

Cov.:

AF XY:

0.00210

AC XY:

1521

AN XY:

725906

show subpopulations

African (AFR)

AF:

0.000330

AC:

AN:

33360

American (AMR)

AF:

0.000135

AC:

AN:

44368

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25990

East Asian (EAS)

AF:

0.00

AC:

AN:

39626

South Asian (SAS)

AF:

0.00158

AC:

136

AN:

86056

European-Finnish (FIN)

AF:

0.000338

AC:

AN:

53314

Middle Eastern (MID)

AF:

0.000522

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00249

AC:

2770

AN:

1110656

Other (OTH)

AF:

0.00178

AC:

107

AN:

60220

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

153

306

458

611

764

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

106

212

318

424

530

<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:

0.00129

AC:

196

AN:

152054

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.000626

AC:

AN:

41544

American (AMR)

AF:

0.0000656

AC:

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00145

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00239

AC:

162

AN:

67862

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

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:

0.00183

Hom.:

Bravo

AF:

0.00124

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.00162

AC:

ESP6500EA

AF:

0.00281

AC:

ExAC

AF:

0.00122

AC:

147

EpiCase

AF:

0.00159

EpiControl

AF:

0.00190

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Catecholaminergic polymorphic ventricular tachycardia 5 (3)

not specified (2)

Cardiovascular phenotype (1)

Catecholaminergic polymorphic ventricular tachycardia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.45

M_CAP

Benign

0.012

MetaRNN

Benign

0.014

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

PhyloP100

3.0

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.82

REVEL

Benign

0.054

Sift

Pathogenic

0.0

Sift4G

Benign

0.20

Polyphen

1.0

Vest4

0.32

MVP

0.10

ClinPred

0.057

GERP RS

4.4

Varity_R

0.40

gMVP

0.0056

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.84

dbscSNV1_RF

Benign

0.57

SpliceAI score (max)

0.13

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