6-123352527-AT-ATT

Position:

• chr6-123352527-AT-ATT

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PVS1_Moderate PM2 BP6 BS1

The NM_001251987.2(TRDN):​c.1383dupA​(p.Ter462fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000528 in 1,592,678 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (0 hom.)
• Consequence: TRDN NM_001251987.2 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.05

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 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.
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 6-123352527-A-AT is Benign according to our data. Variant chr6-123352527-A-AT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 229346.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0015 (226/150548) while in subpopulation AFR AF= 0.00471 (194/41146). AF 95% confidence interval is 0.00417. There are 0 homozygotes in gnomad4. There are 109 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRDN	NM_006073.4	c.1369+11dupA		intron_variant		ENST00000334268.9	NP_006064.2
TRDN	NM_001251987.2	c.1383dupA	p.Ter462fs	frameshift_variant	21/21		NP_001238916.1
TRDN	NM_001407315.1	c.1323dupA	p.Ter442fs	frameshift_variant	20/20		NP_001394244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9	c.1369+11dupA		intron_variant		1	NM_006073.4	ENSP00000333984.5
TRDN	ENST00000662930.1	c.1383dupA	p.Ter462fs	frameshift_variant	21/21			ENSP00000499585.1

Frequencies

GnomAD3 genomes AF: 0.00150 AC: 226 AN: 150436 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00473

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000268

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000962

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000311

Gnomad OTH AF: 0.00244

GnomAD4 exome AF: 0.000426 AC: 615 AN: 1442130 Hom.: 0 Cov.: 34 AF XY: 0.000406 AC XY: 291 AN XY: 717114

Gnomad4 AFR exome AF: 0.00560

Gnomad4 AMR exome AF: 0.000466

Gnomad4 ASJ exome AF: 0.0000787

Gnomad4 EAS exome AF: 0.000129

Gnomad4 SAS exome AF: 0.000251

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.000314

Gnomad4 OTH exome AF: 0.000572

GnomAD4 genome AF: 0.00150 AC: 226 AN: 150548 Hom.: 0 Cov.: 32 AF XY: 0.00148 AC XY: 109 AN XY: 73494

Gnomad4 AFR AF: 0.00471

Gnomad4 AMR AF: 0.000267

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000962

Gnomad4 NFE AF: 0.000311

Gnomad4 OTH AF: 0.00242

Bravo AF: 0.00160

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 30, 2015	Variant classified as Uncertain Significance - Favor Benign. The p.X462fs varian t in TRDN is predicted to cause a frameshift, which alters the protein?s termina tion codon and extends the protein's sequence 28 amino acids downstream. This va riant has not been previously reported in individuals with cardiomyopathy, but h as been identified in several control cohorts at varying frequencies including 0 .4% (44/9742) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs537388823). The TRDN gene has been impli cated in autosomal recessive CPVT and LQTS and the variant's frequency is not hi gh enough to confidently rule out a role in recessive disease. In summary, the p .X462fs variant is suspected to be more likely benign but additional data is nee ded to rule out a role in disease. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 23, 2023	Variant summary: TRDN c.1369+11dupA alters a conserved nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00077 in 209292 control chromosomes, predominantly at a frequency of 0.0065 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in TRDN causing Catecholaminergic Polymorphic Ventricular Tachycardia phenotype (0.0016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.1369+11dupA in individuals affected with Catecholaminergic Polymorphic Ventricular Tachycardia and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as benign, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs537388823; hg19: chr6-123673672;