rs1085307100

Variant names:

• chr6-123512344-AT-A
• rs1085307100
• NM_006073.4:c.568delA

Your query was ambiguous. Multiple possible variants found:

• chr6-123512344-AT-A
• chr6-123512344-AT-ATT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_006073.4(TRDN):​c.568delA​(p.Ile190LeufsTer33) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000222 in 1,353,032 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 0.0000022 (0 hom.)
• Consequence: TRDN NM_006073.4 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0100
• 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 Gene-Disease associations (from GenCC):

• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• catecholaminergic polymorphic ventricular tachycardia 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• familial long QT syndrome

  Inheritance: AR Classification: STRONG Submitted by: G2P
• long QT syndrome

  Inheritance: AR Classification: STRONG Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 10 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

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.568delA	p.Ile190LeufsTer33	frameshift	Exon 7 of 41	NP_006064.2	Q13061-1
	TRDN	NM_001251987.2		c.568delA	p.Ile190LeufsTer33	frameshift	Exon 7 of 21	NP_001238916.1	A0A590UJV0
	TRDN	NM_001407315.1		c.568delA	p.Ile190LeufsTer33	frameshift	Exon 7 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.568delA	p.Ile190LeufsTer33	frameshift	Exon 7 of 41	ENSP00000333984.5	Q13061-1
	TRDN	ENST00000628709.2	TSL:1	c.568delA	p.Ile190LeufsTer33	frameshift	Exon 7 of 9	ENSP00000486095.1	Q13061-2
	TRDN	ENST00000546248.6	TSL:1	c.568delA	p.Ile190LeufsTer33	frameshift	Exon 7 of 8	ENSP00000439281.2	H9ME53

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000222 AC: 3 AN: 1353032 Hom.: 0 Cov.: 26 AF XY: 0.00000297 AC XY: 2 AN XY: 672982

⚠️ 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: 31336

American (AMR) AF: 0.00 AC: 0 AN: 38924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24760

East Asian (EAS) AF: 0.00 AC: 0 AN: 37988

South Asian (SAS) AF: 0.00 AC: 0 AN: 78380

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5486

European-Non Finnish (NFE) AF: 0.00000291 AC: 3 AN: 1029362

Other (OTH) AF: 0.00 AC: 0 AN: 56182

⚠️ 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		-0.010

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1085307100; hg19: chr6-123833489;