6-123530510-A-G

Variant names:

• chr6-123530510-A-G
• rs1020844292
• NM_006073.4:c.480T>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_006073.4(TRDN):​c.480T>C​(p.Thr160Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. T160T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 9.1e-7 (0 hom.)
• Consequence: TRDN NM_006073.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0500
• 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

ENSG00000285691 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.056).
• BP6: Variant 6-123530510-A-G is Benign according to our data. Variant chr6-123530510-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 415182.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.05 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRDN	NM_006073.4	MANE Select	c.480T>C	p.Thr160Thr	synonymous	Exon 5 of 41	NP_006064.2
	TRDN	NM_001251987.2		c.480T>C	p.Thr160Thr	synonymous	Exon 5 of 21	NP_001238916.1
	TRDN	NM_001407315.1		c.480T>C	p.Thr160Thr	synonymous	Exon 5 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.480T>C	p.Thr160Thr	synonymous	Exon 5 of 41	ENSP00000333984.5
	TRDN	ENST00000628709.2	TSL:1	c.480T>C	p.Thr160Thr	synonymous	Exon 5 of 9	ENSP00000486095.1
	TRDN	ENST00000546248.6	TSL:1	c.480T>C	p.Thr160Thr	synonymous	Exon 5 of 8	ENSP00000439281.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096816 Hom.: 0 Cov.: 19 AF XY: 0.00000185 AC XY: 1 AN XY: 540346

⚠️ 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: 22498

American (AMR) AF: 0.00 AC: 0 AN: 17624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19802

East Asian (EAS) AF: 0.00 AC: 0 AN: 26916

South Asian (SAS) AF: 0.00 AC: 0 AN: 56806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4116

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 864654

Other (OTH) AF: 0.0000222 AC: 1 AN: 45070

⚠️ 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.: 33

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	6.0
DANN	Benign	0.70
PhyloP100		-0.050
PromoterAI		0.014	Neutral

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: rs1020844292; hg19: chr6-123851655;