6-123393619-C-T

Variant names:

• chr6-123393619-C-T
• rs41284430
• NM_006073.4:c.1105+5G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006073.4(TRDN):​c.1105+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0436 in 1,599,324 control chromosomes in the GnomAD database, including 1,732 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (122 hom., cov: 32)
  • Exomes 𝑓: 0.045 (1610 hom.)
• Consequence: TRDN NM_006073.4 splice_region, intron
• Scores: Splicing: ADA: 0.4824
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0620
• Publications: 3 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 6-123393619-C-T is Benign according to our data. Variant chr6-123393619-C-T is described in ClinVar as Benign. ClinVar VariationId is 227105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.052 is higher than 0.05.

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+5G>A		splice_region intron	N/A	NP_006064.2	Q13061-1
	TRDN	NM_001251987.2		c.1108+5G>A		splice_region intron	N/A	NP_001238916.1	A0A590UJV0
	TRDN	NM_001407315.1		c.1048+5G>A		splice_region 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+5G>A		splice_region intron	N/A	ENSP00000333984.5	Q13061-1
	TRDN	ENST00000962661.1		c.1108+5G>A		splice_region intron	N/A	ENSP00000632720.1
	TRDN	ENST00000962654.1		c.1108+5G>A		splice_region intron	N/A	ENSP00000632713.1

Frequencies

GnomAD3 genomes AF: 0.0320 AC: 4860 AN: 151918 Hom.: 122 Cov.: 32

Gnomad AFR AF: 0.00967

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.0269

Gnomad ASJ AF: 0.0208

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00850

Gnomad FIN AF: 0.0290

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0512

Gnomad OTH AF: 0.0354

GnomAD2 exomes AF: 0.0317 AC: 7284 AN: 229690 AF XY: 0.0320

Gnomad AFR exome AF: 0.00666

Gnomad AMR exome AF: 0.0226

Gnomad ASJ exome AF: 0.0198

Gnomad EAS exome AF: 0.000117

Gnomad FIN exome AF: 0.0315

Gnomad NFE exome AF: 0.0499

Gnomad OTH exome AF: 0.0374

GnomAD4 exome AF: 0.0448 AC: 64862 AN: 1447288 Hom.: 1610 Cov.: 30 AF XY: 0.0438 AC XY: 31493 AN XY: 718744

African (AFR) AF: 0.00724 AC: 240 AN: 33168

American (AMR) AF: 0.0250 AC: 1077 AN: 43160

Ashkenazi Jewish (ASJ) AF: 0.0197 AC: 505 AN: 25652

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39502

South Asian (SAS) AF: 0.0118 AC: 988 AN: 84008

European-Finnish (FIN) AF: 0.0320 AC: 1684 AN: 52564

Middle Eastern (MID) AF: 0.0351 AC: 201 AN: 5730

European-Non Finnish (NFE) AF: 0.0524 AC: 57833 AN: 1103842

Other (OTH) AF: 0.0391 AC: 2330 AN: 59662

GnomAD4 genome AF: 0.0320 AC: 4862 AN: 152036 Hom.: 122 Cov.: 32 AF XY: 0.0295 AC XY: 2190 AN XY: 74328

African (AFR) AF: 0.00967 AC: 401 AN: 41486

American (AMR) AF: 0.0269 AC: 411 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0208 AC: 72 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00850 AC: 41 AN: 4822

European-Finnish (FIN) AF: 0.0290 AC: 307 AN: 10586

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0512 AC: 3477 AN: 67918

Other (OTH) AF: 0.0350 AC: 74 AN: 2114

Alfa AF: 0.0431 Hom.: 331

Bravo AF: 0.0316

Asia WGS AF: 0.00779 AC: 28 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	13
DANN	Benign	0.72
PhyloP100		0.062
Mutation Taster		=91/9	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.48
dbscSNV1_RF	Benign	0.51
SpliceAI score (max)		0.48		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.48		Position offset: 5

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

Other links and lift over

dbSNP: rs41284430; hg19: chr6-123714764;