Genetic Variant TRDN:p.Pro284Gln (chr6-123497195-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_006073.4(TRDN):c.851C>A(p.Pro284Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000716 in 1,396,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. P284R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

TRDN
NM_006073.4 missense, splice_region

Scores

Splicing: ADA: 0.9547

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.11

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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.38132876).

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.851C>A	p.Pro284Gln	missense splice_region	Exon 9 of 41	NP_006064.2	Q13061-1
TRDN	NM_001251987.2		c.851C>A	p.Pro284Gln	missense splice_region	Exon 9 of 21	NP_001238916.1	A0A590UJV0
TRDN	NM_001407315.1		c.793+6524C>A		intron	N/A	NP_001394244.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRDN	ENST00000334268.9	TSL:1 MANE Select	c.851C>A	p.Pro284Gln	missense splice_region	Exon 9 of 41	ENSP00000333984.5	Q13061-1
TRDN	ENST00000628709.2	TSL:1	c.793+6524C>A		intron	N/A	ENSP00000486095.1	Q13061-2
TRDN	ENST00000962661.1		c.851C>A	p.Pro284Gln	missense splice_region	Exon 9 of 41	ENSP00000632720.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.16e-7

AC:

AN:

1396074

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

690492

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30412

American (AMR)

AF:

0.00

AC:

AN:

33568

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24606

East Asian (EAS)

AF:

0.00

AC:

AN:

36012

South Asian (SAS)

AF:

0.00

AC:

AN:

77308

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50740

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5636

European-Non Finnish (NFE)

AF:

9.26e-7

AC:

AN:

1080162

Other (OTH)

AF:

0.00

AC:

AN:

57630

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Uncertain

0.098

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.57

M_CAP

Benign

0.042

MetaRNN

Benign

0.38

MetaSVM

Benign

-0.54

MutationAssessor

Benign

0.81

PhyloP100

5.1

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.1

REVEL

Benign

0.19

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.031

Polyphen

1.0

Vest4

0.37

MutPred

0.27

Loss of catalytic residue at K283 (P = 0.1079)

MVP

0.48

ClinPred

0.85

GERP RS

6.0

Varity_R

0.37

gMVP

0.031

Mutation Taster

=65/35

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.95

dbscSNV1_RF

Pathogenic

0.79

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over