6-123393622-AC-A

Variant names:

• chr6-123393622-AC-A
• rs1772598763
• NM_006073.4:c.1105+1delG

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_006073.4(TRDN):​c.1105+1delG variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,449,914 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TRDN NM_006073.4 splice_donor, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.37
• 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-AS1 (HGNC:40592): (TRDN antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.024657534 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.5, offset of 0 (no position change), new splice context is: caaGTaagc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• 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.1105+1delG		splice_donor intron	N/A	NP_006064.2	Q13061-1
	TRDN	NM_001251987.2		c.1108+1delG		splice_donor intron	N/A	NP_001238916.1	A0A590UJV0
	TRDN	NM_001407315.1		c.1048+1delG		splice_donor intron	N/A	NP_001394244.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRDN	ENST00000334268.9	TSL:1 MANE Select	c.1105+1delG		splice_donor intron	N/A	ENSP00000333984.5	Q13061-1
	TRDN	ENST00000962661.1		c.1108+1delG		splice_donor intron	N/A	ENSP00000632720.1
	TRDN	ENST00000962654.1		c.1108+1delG		splice_donor intron	N/A	ENSP00000632713.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1449914 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 720196

African (AFR) AF: 0.00 AC: 0 AN: 33254

American (AMR) AF: 0.0000460 AC: 2 AN: 43446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25722

East Asian (EAS) AF: 0.00 AC: 0 AN: 39532

South Asian (SAS) AF: 0.00 AC: 0 AN: 84378

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52676

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105346

Other (OTH) AF: 0.0000167 AC: 1 AN: 59820

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

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
PhyloP100		2.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: 3
DS_DL_spliceai		0.97		Position offset: 2

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

Other links and lift over

dbSNP: rs1772598763; hg19: chr6-123714767;