6-123377897-T-A

Variant names:

• chr6-123377897-T-A
• NM_006073.4:c.1188A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006073.4(TRDN):​c.1188A>T​(p.Lys396Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000226 in 1,324,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Synonymous variant affecting the same amino acid position (i.e. K396K) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: TRDN NM_006073.4 missense, splice_region
• Scores: Splicing: ADA: 0.07536
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.10

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08392024).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRDN	NM_006073.4	c.1188A>T	p.Lys396Asn	missense_variant, splice_region_variant	Exon 17 of 41	ENST00000334268.9	NP_006064.2
TRDN	NM_001251987.2	c.1191A>T	p.Lys397Asn	missense_variant, splice_region_variant	Exon 17 of 21		NP_001238916.1
TRDN	NM_001407315.1	c.1131A>T	p.Lys377Asn	missense_variant, splice_region_variant	Exon 16 of 20		NP_001394244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9	c.1188A>T	p.Lys396Asn	missense_variant, splice_region_variant	Exon 17 of 41	1	NM_006073.4	ENSP00000333984.5
TRDN	ENST00000662930.1	c.1191A>T	p.Lys397Asn	missense_variant, splice_region_variant	Exon 17 of 21			ENSP00000499585.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000226 AC: 3 AN: 1324700 Hom.: 0 Cov.: 24 AF XY: 0.00000456 AC XY: 3 AN XY: 657596

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: 0.00000295

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.021
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.059	T
Polyphen		0.053	B
Vest4		0.27
MutPred		0.22		Loss of methylation at K396 (P = 0.0029);
MVP		0.17
ClinPred		0.85	D
GERP RS		3.8
Varity_R		0.21
gMVP		0.0059

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.075
dbscSNV1_RF	Benign	0.33
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-123699042;