6-123464887-GAAA-GAAAA

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PVS1_Moderate BP6_Moderate

The NM_001256020.2(TRDN):​c.889dupT​(p.Ser297PhefsTer32) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,399,904 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (0 hom.)
• Consequence: TRDN NM_001256020.2 frameshift
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Uncertain_significance. The variant received 0 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-G-GA is Benign according to our data. Variant chr6-123464887-G-GA is described in ClinVar as Benign. ClinVar VariationId is 1599217.Status of the report is criteria_provided_single_submitter, 1 stars.

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+18dupT		intron	N/A	NP_006064.2
	TRDN	NM_001256020.2		c.889dupT	p.Ser297PhefsTer32	frameshift	Exon 9 of 9	NP_001242949.1
	TRDN	NM_001251987.2		c.931+18dupT		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.889dupT	p.Ser297PhefsTer32	frameshift	Exon 9 of 9	ENSP00000486095.1
	TRDN	ENST00000334268.9	TSL:1 MANE Select	c.931+18dupT		intron	N/A	ENSP00000333984.5
	TRDN	ENST00000962661.1		c.931+18dupT		intron	N/A	ENSP00000632720.1

Frequencies

GnomAD3 genomes AF: 0.000121 AC: 18 AN: 148214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000164

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00338 AC: 363 AN: 107382 AF XY: 0.00308

Gnomad AFR exome AF: 0.00169

Gnomad AMR exome AF: 0.00658

Gnomad ASJ exome AF: 0.00205

Gnomad EAS exome AF: 0.00313

Gnomad FIN exome AF: 0.000875

Gnomad NFE exome AF: 0.00355

Gnomad OTH exome AF: 0.00530

GnomAD4 exome AF: 0.00179 AC: 2237 AN: 1251612 Hom.: 0 Cov.: 31 AF XY: 0.00184 AC XY: 1132 AN XY: 616066

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00176 AC: 50 AN: 28448

American (AMR) AF: 0.00393 AC: 121 AN: 30800

Ashkenazi Jewish (ASJ) AF: 0.00309 AC: 67 AN: 21682

East Asian (EAS) AF: 0.00190 AC: 60 AN: 31614

South Asian (SAS) AF: 0.00358 AC: 241 AN: 67364

European-Finnish (FIN) AF: 0.00231 AC: 101 AN: 43764

Middle Eastern (MID) AF: 0.00156 AC: 8 AN: 5140

European-Non Finnish (NFE) AF: 0.00153 AC: 1482 AN: 971668

Other (OTH) AF: 0.00209 AC: 107 AN: 51132

⚠️ 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 AF: 0.000121 AC: 18 AN: 148292 Hom.: 0 Cov.: 32 AF XY: 0.000138 AC XY: 10 AN XY: 72210

African (AFR) AF: 0.000124 AC: 5 AN: 40482

American (AMR) AF: 0.00 AC: 0 AN: 14836

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: 0.000104 AC: 1 AN: 9618

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

European-Non Finnish (NFE) AF: 0.000164 AC: 11 AN: 66912

Other (OTH) AF: 0.00 AC: 0 AN: 2044

Alfa AF: 0.0129 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: 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
PhyloP100		-1.3
Mutation Taster		=99/1	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: COSV105224741; COSMIC: COSV105224741;