rs9490809

Positions:

• chr6-123548462-G-A
• chr6-123548462-G-C
• chr6-123548462-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006073.4(TRDN):​c.383C>T​(p.Thr128Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000128 in 1,559,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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. T128S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0810

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042642176).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRDN	NM_006073.4	c.383C>T	p.Thr128Ile	missense_variant	3/41	ENST00000334268.9
LOC105377982	XR_001743833.2	n.2346-4894G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRDN	ENST00000334268.9	c.383C>T	p.Thr128Ile	missense_variant	3/41	1	NM_006073.4	A2
	ENST00000648704.1	n.449-4960G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151412 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000659

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1407770 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 697608

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.20e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151412 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 73916

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000659

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	4.5
DANN	Benign	0.48
DEOGEN2	Benign	0.085	T;.;.;.
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.56	T;T;T;T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.043	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.56	N;N;.;N
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.33	N;.;N;N
REVEL	Benign	0.019
Sift	Benign	0.39	T;.;T;T
Sift4G	Benign	0.30	T;T;T;T
Polyphen		0.0020	B;.;.;.
Vest4		0.059
MutPred		0.28		Loss of phosphorylation at T128 (P = 0.0069);Loss of phosphorylation at T128 (P = 0.0069);Loss of phosphorylation at T128 (P = 0.0069);Loss of phosphorylation at T128 (P = 0.0069);
MVP		0.15
ClinPred		0.029	T
GERP RS		2.0
Varity_R		0.030
gMVP		0.010

Splicing

Name	Calibrated prediction	Score	Prediction
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

LitVar

Other links and lift over

dbSNP: rs9490809; hg19: chr6-123869607;