Genetic Variant NM_006073.4:c.1099G>A (chr6-123393630-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006073.4(TRDN):c.1099G>A(p.Ala367Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A367S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TRDN
NM_006073.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0500

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 links:

TRDN-AS1 (HGNC:40592): (TRDN antisense RNA 1)

TRDN-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.045713335).

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.1099G>A	p.Ala367Thr	missense	Exon 13 of 41	NP_006064.2	Q13061-1
TRDN	NM_001251987.2		c.1102G>A	p.Ala368Thr	missense	Exon 13 of 21	NP_001238916.1	A0A590UJV0
TRDN	NM_001407315.1		c.1042G>A	p.Ala348Thr	missense	Exon 12 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.1099G>A	p.Ala367Thr	missense	Exon 13 of 41	ENSP00000333984.5	Q13061-1
TRDN	ENST00000962661.1		c.1102G>A	p.Ala368Thr	missense	Exon 13 of 41	ENSP00000632720.1
TRDN	ENST00000962654.1		c.1102G>A	p.Ala368Thr	missense	Exon 13 of 41	ENSP00000632713.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1451890

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721350

African (AFR)

AF:

0.00

AC:

AN:

33284

American (AMR)

AF:

0.00

AC:

AN:

43732

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25770

East Asian (EAS)

AF:

0.00

AC:

AN:

39542

South Asian (SAS)

AF:

0.00

AC:

AN:

84712

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52776

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106418

Other (OTH)

AF:

0.00

AC:

AN:

59914

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.79

CADD

Benign

7.1

(source)

DANN

Benign

0.59

DEOGEN2

Benign

0.074

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.50

M_CAP

Benign

0.012

MetaRNN

Benign

0.046

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.34

PhyloP100

0.050

PrimateAI

Benign

0.30

PROVEAN

Benign

0.020

REVEL

Benign

0.023

Sift

Benign

0.68

Sift4G

Benign

0.58

Polyphen

0.0010

Vest4

0.13

MutPred

0.28

Gain of phosphorylation at A367 (P = 0.0233)

MVP

0.040

ClinPred

0.030

GERP RS

0.99

Varity_R

0.037

gMVP

0.0093

Mutation Taster

=97/3

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over