ENST00000628709.2:c.888_889dupTT

Variant names:

• chr6-123464887-G-GAA
• rs201431159
• ENST00000628709.2:c.888_889dupTT

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The ENST00000628709.2(TRDN):​c.888_889dupTT​(p.Ser297PhefsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000023 in 1,305,884 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: TRDN ENST00000628709.2 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.26
• 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 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00559 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000628709.2. 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.931+17_931+18dupTT		intron	N/A	NP_006064.2
	TRDN	NM_001256020.2		c.888_889dupTT	p.Ser297PhefsTer9	frameshift	Exon 9 of 9	NP_001242949.1
	TRDN	NM_001251987.2		c.931+17_931+18dupTT		intron	N/A	NP_001238916.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRDN	ENST00000628709.2	TSL:1	c.888_889dupTT	p.Ser297PhefsTer9	frameshift	Exon 9 of 9	ENSP00000486095.1
	TRDN	ENST00000334268.9	TSL:1 MANE Select	c.931+17_931+18dupTT		intron	N/A	ENSP00000333984.5
	TRDN	ENST00000962661.1		c.931+17_931+18dupTT		intron	N/A	ENSP00000632720.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000230 AC: 3 AN: 1305884 Hom.: 0 Cov.: 31 AF XY: 0.00000155 AC XY: 1 AN XY: 643336

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29638

American (AMR) AF: 0.00 AC: 0 AN: 32560

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22798

East Asian (EAS) AF: 0.00 AC: 0 AN: 33470

South Asian (SAS) AF: 0.00 AC: 0 AN: 71572

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45806

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5330

European-Non Finnish (NFE) AF: 0.00000297 AC: 3 AN: 1011138

Other (OTH) AF: 0.00 AC: 0 AN: 53572

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.3

Splicing

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

Other links and lift over

dbSNP: rs201431159; hg19: chr6-123786032;