chr6-123438944-C-A

Variant names:

• chr6-123438944-C-A
• rs763851599
• NM_006073.4:c.991G>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1 PM2 PP3_Strong

The NM_006073.4(TRDN):​c.991G>T​(p.Glu331*) variant causes a stop gained, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TRDN NM_006073.4 stop_gained, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.13
• 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: Pathogenic. The variant received 14 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRDN	NM_006073.4	MANE Select	c.991G>T	p.Glu331*	stop_gained splice_region	Exon 11 of 41	NP_006064.2	Q13061-1
	TRDN	NM_001251987.2		c.991G>T	p.Ala331Ser	missense splice_region	Exon 11 of 21	NP_001238916.1	A0A590UJV0
	TRDN	NM_001407315.1		c.931G>T	p.Ala311Ser	missense splice_region	Exon 10 of 20	NP_001394244.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRDN	ENST00000334268.9	TSL:1 MANE Select	c.991G>T	p.Glu331*	stop_gained splice_region	Exon 11 of 41	ENSP00000333984.5	Q13061-1
	TRDN	ENST00000962661.1		c.991G>T	p.Ala331Ser	missense splice_region	Exon 11 of 41	ENSP00000632720.1
	TRDN	ENST00000962654.1		c.991G>T	p.Ala331Ser	missense splice_region	Exon 11 of 41	ENSP00000632713.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1405754 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 694526

African (AFR) AF: 0.00 AC: 0 AN: 32090

American (AMR) AF: 0.00 AC: 0 AN: 36054

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25144

East Asian (EAS) AF: 0.00 AC: 0 AN: 37676

South Asian (SAS) AF: 0.00 AC: 0 AN: 79170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5680

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1081590

Other (OTH) AF: 0.00 AC: 0 AN: 58180

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	53
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		4.1
Vest4		0.71
GERP RS		5.1
Mutation Taster		=16/184	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.87		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.87		Position offset: 0

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

Other links and lift over

dbSNP: rs763851599; hg19: chr6-123760089;