6-123316507-C-T

Position:

• chr6-123316507-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_006073.4(TRDN):​c.1472-12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000215 in 1,608,810 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: TRDN NM_006073.4 intron
• Scores: Splicing: ADA: 0.00004022
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.495

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]

LOC124901393 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 6-123316507-C-T is Benign according to our data. Variant chr6-123316507-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 229349.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}. Variant chr6-123316507-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRDN	NM_006073.4	c.1472-12G>A		intron_variant		ENST00000334268.9	NP_006064.2
LOC124901393	XR_007059734.1	n.81+7070C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9	c.1472-12G>A		intron_variant		1	NM_006073.4	ENSP00000333984.5

Frequencies

GnomAD3 genomes AF: 0.000376 AC: 57 AN: 151490 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000412

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000662

Gnomad ASJ AF: 0.00462

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000295

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000202 AC: 50 AN: 246932 Hom.: 0 AF XY: 0.000179 AC XY: 24 AN XY: 134004

Gnomad AFR exome AF: 0.000326

Gnomad AMR exome AF: 0.0000585

Gnomad ASJ exome AF: 0.00241

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000152

Gnomad OTH exome AF: 0.000334

GnomAD4 exome AF: 0.000198 AC: 289 AN: 1457202 Hom.: 1 Cov.: 30 AF XY: 0.000193 AC XY: 140 AN XY: 724950

Gnomad4 AFR exome AF: 0.000662

Gnomad4 AMR exome AF: 0.000113

Gnomad4 ASJ exome AF: 0.00331

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000127

Gnomad4 OTH exome AF: 0.000466

GnomAD4 genome AF: 0.000376 AC: 57 AN: 151608 Hom.: 0 Cov.: 32 AF XY: 0.000284 AC XY: 21 AN XY: 74066

Gnomad4 AFR AF: 0.000410

Gnomad4 AMR AF: 0.0000661

Gnomad4 ASJ AF: 0.00462

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000295

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.000684 Hom.: 0

Bravo AF: 0.000306

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 21, 2015

The c.1472-12G>A variant in TRDN has not been previously reported in individuals with cardiomyopathy, but has been identified in 20/65850 European chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs375364108). This variant is located in the 3' splice region. Computational too ls do not suggest an impact to splicing. However, this information is not predic tive enough to rule out pathogenicity. In summary, the clinical significance of the c.1472-12G>A variant is uncertain. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 15, 2020

- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.1
DANN	Benign	0.43

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000040
dbscSNV1_RF	Benign	0.012
SpliceAI score (max)		0.020		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: rs375364108; hg19: chr6-123637652;