chr6-123377897-T-C

Variant names:

• chr6-123377897-T-C
• rs6901953
• NM_006073.4:c.1188A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_006073.4(TRDN):​c.1188A>G​(p.Lys396Lys) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 1,470,594 control chromosomes in the GnomAD database, including 95,898 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9543 hom., cov: 32)
  • Exomes 𝑓: 0.35 (86355 hom.)
• Consequence: TRDN NM_006073.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.002327
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.10
• Publications: 12 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: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• catecholaminergic polymorphic ventricular tachycardia 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• familial long QT syndrome

  Inheritance: AR Classification: STRONG Submitted by: G2P
• long QT syndrome

  Inheritance: AR Classification: STRONG Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 6-123377897-T-C is Benign according to our data. Variant chr6-123377897-T-C is described in ClinVar as Benign. ClinVar VariationId is 227106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.398 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.1188A>G	p.Lys396Lys	splice_region synonymous	Exon 17 of 41	NP_006064.2	Q13061-1
	TRDN	NM_001251987.2		c.1191A>G	p.Lys397Lys	splice_region synonymous	Exon 17 of 21	NP_001238916.1	A0A590UJV0
	TRDN	NM_001407315.1		c.1131A>G	p.Lys377Lys	splice_region synonymous	Exon 16 of 20	NP_001394244.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRDN	ENST00000334268.9	TSL:1 MANE Select	c.1188A>G	p.Lys396Lys	splice_region synonymous	Exon 17 of 41	ENSP00000333984.5	Q13061-1
	TRDN	ENST00000962661.1		c.1191A>G	p.Lys397Lys	splice_region synonymous	Exon 17 of 41	ENSP00000632720.1
	TRDN	ENST00000962654.1		c.1188A>G	p.Lys396Lys	splice_region synonymous	Exon 17 of 41	ENSP00000632713.1

Frequencies

GnomAD3 genomes AF: 0.346 AC: 52611 AN: 151980 Hom.: 9526 Cov.: 32

Gnomad AFR AF: 0.338

Gnomad AMI AF: 0.271

Gnomad AMR AF: 0.406

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.265

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.378

Gnomad OTH AF: 0.387

GnomAD2 exomes AF: 0.333 AC: 52080 AN: 156336 AF XY: 0.323

Gnomad AFR exome AF: 0.345

Gnomad AMR exome AF: 0.414

Gnomad ASJ exome AF: 0.394

Gnomad EAS exome AF: 0.119

Gnomad FIN exome AF: 0.289

Gnomad NFE exome AF: 0.389

Gnomad OTH exome AF: 0.378

GnomAD4 exome AF: 0.355 AC: 467949 AN: 1318496 Hom.: 86355 Cov.: 24 AF XY: 0.349 AC XY: 228237 AN XY: 654760

African (AFR) AF: 0.340 AC: 9966 AN: 29330

American (AMR) AF: 0.411 AC: 14272 AN: 34704

Ashkenazi Jewish (ASJ) AF: 0.395 AC: 9658 AN: 24474

East Asian (EAS) AF: 0.140 AC: 4989 AN: 35734

South Asian (SAS) AF: 0.176 AC: 13442 AN: 76212

European-Finnish (FIN) AF: 0.287 AC: 13833 AN: 48146

Middle Eastern (MID) AF: 0.367 AC: 1575 AN: 4288

European-Non Finnish (NFE) AF: 0.377 AC: 380903 AN: 1010336

Other (OTH) AF: 0.349 AC: 19311 AN: 55272

GnomAD4 genome AF: 0.346 AC: 52661 AN: 152098 Hom.: 9543 Cov.: 32 AF XY: 0.336 AC XY: 24970 AN XY: 74330

African (AFR) AF: 0.337 AC: 13999 AN: 41496

American (AMR) AF: 0.406 AC: 6198 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 1393 AN: 3472

East Asian (EAS) AF: 0.115 AC: 595 AN: 5184

South Asian (SAS) AF: 0.161 AC: 777 AN: 4820

European-Finnish (FIN) AF: 0.265 AC: 2805 AN: 10582

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.378 AC: 25697 AN: 67970

Other (OTH) AF: 0.390 AC: 824 AN: 2112

Alfa AF: 0.375 Hom.: 28711

Bravo AF: 0.361

Asia WGS AF: 0.192 AC: 670 AN: 3476

ClinVar

ClinVar submissions

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)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	13
DANN	Benign	0.90
PhyloP100		1.1
Mutation Taster		=54/46	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0023
dbscSNV1_RF	Benign	0.13
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: rs6901953; hg19: chr6-123699042;