6-123464887-GAAA-GAA

Variant names:

• chr6-123464887-GA-G
• rs201431159
• ENST00000628709.2:c.889delT

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PVS1_Moderate BP6_Very_Strong BS1 BS2

The NM_001256020.2(TRDN):​c.889delT​(p.Ser297LeufsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000956 in 1,450,828 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (1 hom.)
• Consequence: TRDN NM_001256020.2 frameshift
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.26
• Publications: 7 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 -14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00559 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BP6: Variant 6-123464887-GA-G is Benign according to our data. Variant chr6-123464887-GA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00416 (617/148304) while in subpopulation AFR AF = 0.0145 (586/40484). AF 95% confidence interval is 0.0135. There are 5 homozygotes in GnomAd4. There are 261 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256020.2. 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.931+18delT		intron	N/A	NP_006064.2
	TRDN	NM_001256020.2		c.889delT	p.Ser297LeufsTer8	frameshift	Exon 9 of 9	NP_001242949.1
	TRDN	NM_001251987.2		c.931+18delT		intron	N/A	NP_001238916.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRDN	ENST00000628709.2	TSL:1	c.889delT	p.Ser297LeufsTer8	frameshift	Exon 9 of 9	ENSP00000486095.1
	TRDN	ENST00000334268.9	TSL:1 MANE Select	c.931+18delT		intron	N/A	ENSP00000333984.5
	TRDN	ENST00000962661.1		c.931+18delT		intron	N/A	ENSP00000632720.1

Frequencies

GnomAD3 genomes AF: 0.00415 AC: 615 AN: 148224 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00121

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000747

Gnomad OTH AF: 0.00346

GnomAD2 exomes AF: 0.00461 AC: 495 AN: 107382 AF XY: 0.00427

Gnomad AFR exome AF: 0.0248

Gnomad AMR exome AF: 0.00226

Gnomad ASJ exome AF: 0.00260

Gnomad EAS exome AF: 0.00339

Gnomad FIN exome AF: 0.00123

Gnomad NFE exome AF: 0.00480

Gnomad OTH exome AF: 0.00459

GnomAD4 exome AF: 0.000591 AC: 770 AN: 1302524 Hom.: 1 Cov.: 31 AF XY: 0.000517 AC XY: 332 AN XY: 641568

African (AFR) AF: 0.0144 AC: 426 AN: 29540

American (AMR) AF: 0.00145 AC: 47 AN: 32352

Ashkenazi Jewish (ASJ) AF: 0.000176 AC: 4 AN: 22696

East Asian (EAS) AF: 0.000210 AC: 7 AN: 33374

South Asian (SAS) AF: 0.000521 AC: 37 AN: 71048

European-Finnish (FIN) AF: 0.000395 AC: 18 AN: 45590

Middle Eastern (MID) AF: 0.00151 AC: 8 AN: 5312

European-Non Finnish (NFE) AF: 0.000185 AC: 187 AN: 1009196

Other (OTH) AF: 0.000674 AC: 36 AN: 53416

GnomAD4 genome AF: 0.00416 AC: 617 AN: 148304 Hom.: 5 Cov.: 32 AF XY: 0.00361 AC XY: 261 AN XY: 72220

African (AFR) AF: 0.0145 AC: 586 AN: 40484

American (AMR) AF: 0.00121 AC: 18 AN: 14838

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3432

East Asian (EAS) AF: 0.000197 AC: 1 AN: 5086

South Asian (SAS) AF: 0.00 AC: 0 AN: 4698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000747 AC: 5 AN: 66908

Other (OTH) AF: 0.00342 AC: 7 AN: 2046

Alfa AF: 0.00277 Hom.: 0

Bravo AF: 0.00467

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	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
PhyloP100		-1.3
Mutation Taster		=189/11	polymorphism

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: rs201431159; hg19: chr6-123786032; COSMIC: COSV62113533; COSMIC: COSV62113533;