6-123464887-GAAA-GAAAAA

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRDN	NM_006073.4	c.931+17_931+18dupTT		intron_variant	Intron 10 of 40	ENST00000334268.9	NP_006064.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9	c.931+17_931+18dupTT		intron_variant	Intron 10 of 40	1	NM_006073.4	ENSP00000333984.5

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 = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;