6-123352527-AT-A

Variant names:

• chr6-123352527-AT-A
• rs537388823
• NM_006073.4:c.1369+11delA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_001251987.2(TRDN):​c.1383delA​(p.Lys461AsnfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00019 in 1,436,530 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K461K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TRDN NM_001251987.2 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05
• 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: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• catecholaminergic polymorphic ventricular tachycardia 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• 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: Uncertain_significance. The variant received 2 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 0.00216 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001251987.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRDN	NM_006073.4	MANE Select	c.1369+11delA		intron	N/A	NP_006064.2
	TRDN	NM_001251987.2		c.1383delA	p.Lys461AsnfsTer5	frameshift	Exon 21 of 21	NP_001238916.1
	TRDN	NM_001407315.1		c.1323delA	p.Lys441AsnfsTer5	frameshift	Exon 20 of 20	NP_001394244.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRDN	ENST00000334268.9	TSL:1 MANE Select	c.1369+11delA		intron	N/A	ENSP00000333984.5
	TRDN	ENST00000662930.1		c.1383delA	p.Lys461AsnfsTer5	frameshift	Exon 21 of 21	ENSP00000499585.1
	TRDN	ENST00000962661.1		c.1372+11delA		intron	N/A	ENSP00000632720.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 150430 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00104 AC: 218 AN: 209292 AF XY: 0.00105

Gnomad AFR exome AF: 0.000890

Gnomad AMR exome AF: 0.00183

Gnomad ASJ exome AF: 0.00195

Gnomad EAS exome AF: 0.00108

Gnomad FIN exome AF: 0.000515

Gnomad NFE exome AF: 0.000751

Gnomad OTH exome AF: 0.00144

GnomAD4 exome AF: 0.000190 AC: 273 AN: 1436530 Hom.: 0 Cov.: 34 AF XY: 0.000196 AC XY: 140 AN XY: 714160

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

African (AFR) AF: 0.000459 AC: 15 AN: 32674

American (AMR) AF: 0.00130 AC: 55 AN: 42402

Ashkenazi Jewish (ASJ) AF: 0.000555 AC: 14 AN: 25216

East Asian (EAS) AF: 0.000129 AC: 5 AN: 38626

South Asian (SAS) AF: 0.000446 AC: 37 AN: 82988

European-Finnish (FIN) AF: 0.000192 AC: 10 AN: 52076

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5670

European-Non Finnish (NFE) AF: 0.000109 AC: 120 AN: 1097770

Other (OTH) AF: 0.000271 AC: 16 AN: 59108

⚠️ 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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 150430 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73370

African (AFR) AF: 0.00 AC: 0 AN: 41024

American (AMR) AF: 0.00 AC: 0 AN: 14942

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3436

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4768

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67434

Other (OTH) AF: 0.00 AC: 0 AN: 2048

Alfa AF: 0.00629 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs537388823; hg19: chr6-123673672; COSMIC: COSV62120644;