6-123381381-G-T

Variant names:

• chr6-123381381-G-T
• rs1364039811
• NM_006073.4:c.1175C>A

Variant summary

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

The NM_006073.4(TRDN):​c.1175C>A​(p.Pro392His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000996 in 1,405,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.772

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=0.07608986).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRDN	NM_006073.4	c.1175C>A	p.Pro392His	missense_variant	Exon 16 of 41	ENST00000334268.9	NP_006064.2
TRDN	NM_001251987.2	c.1178C>A	p.Pro393His	missense_variant	Exon 16 of 21		NP_001238916.1
TRDN	NM_001407315.1	c.1118C>A	p.Pro373His	missense_variant	Exon 15 of 20		NP_001394244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9	c.1175C>A	p.Pro392His	missense_variant	Exon 16 of 41	1	NM_006073.4	ENSP00000333984.5
TRDN	ENST00000662930.1	c.1178C>A	p.Pro393His	missense_variant	Exon 16 of 21			ENSP00000499585.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000581 AC: 1 AN: 172038 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 90988

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000384

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000996 AC: 14 AN: 1405434 Hom.: 0 Cov.: 31 AF XY: 0.00000576 AC XY: 4 AN XY: 694128

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000270

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: 0.0000111

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.81	L
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.053
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.033	D
Polyphen		0.025	B
Vest4		0.15
MutPred		0.27		Gain of helix (P = 0.0349);
MVP		0.13
ClinPred		0.37	T
GERP RS		0.96
Varity_R		0.20
gMVP		0.0090

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: rs1364039811; hg19: chr6-123702526;