chr6-123503847-A-T

Variant names:

• chr6-123503847-A-T
• rs758037868
• NM_006073.4:c.665T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006073.4(TRDN):​c.665T>A​(p.Val222Glu) 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. 15/22 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. V222G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.16
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19412187).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRDN	NM_006073.4	c.665T>A	p.Val222Glu	missense_variant	Exon 8 of 41	ENST00000334268.9	NP_006064.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9	c.665T>A	p.Val222Glu	missense_variant	Exon 8 of 41	1	NM_006073.4	ENSP00000333984.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00 AC: 0 AN: 218958 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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 Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.00070	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	20
DANN	Benign	0.93
DEOGEN2	Benign	0.23	T;.;.
Eigen	Benign	-0.078
Eigen_PC	Benign	-0.065
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.3	M;M;.
PhyloP100		2.2
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.1	N;.;N
REVEL	Benign	0.15
Sift	Uncertain	0.0020	D;.;D
Sift4G	Benign	0.082	T;T;T
Polyphen		0.88	P;.;.
Vest4		0.35
MutPred		0.42		Gain of solvent accessibility (P = 0.0078);Gain of solvent accessibility (P = 0.0078);Gain of solvent accessibility (P = 0.0078);
MVP		0.60
ClinPred		0.74	D
GERP RS		1.9
Varity_R		0.37
gMVP		0.017
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs758037868; hg19: chr6-123824992;