ENST00000546248.6:c.854T>C

Variant names:

• chr6-123503658-A-G
• rs572614305
• ENST00000546248.6:c.854T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000546248.6(TRDN):​c.854T>C​(p.Met285Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000333 in 1,606,380 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/10 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00020 (2 hom.)
• Consequence: TRDN ENST00000546248.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: -0.240
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006168872).
• BP6: Variant 6-123503658-A-G is Benign according to our data. Variant chr6-123503658-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 505274.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00163 (248/152132) while in subpopulation AFR AF = 0.0058 (241/41520). AF 95% confidence interval is 0.0052. There are 0 homozygotes in GnomAd4. There are 127 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000546248.6. 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.793+61T>C		intron	N/A	NP_006064.2	Q13061-1
	TRDN	NM_001256021.2		c.854T>C	p.Met285Thr	missense	Exon 8 of 8	NP_001242950.1	H9ME53
	TRDN	NM_001251987.2		c.793+61T>C		intron	N/A	NP_001238916.1	A0A590UJV0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRDN	ENST00000546248.6	TSL:1	c.854T>C	p.Met285Thr	missense	Exon 8 of 8	ENSP00000439281.2	H9ME53
	TRDN	ENST00000334268.9	TSL:1 MANE Select	c.793+61T>C		intron	N/A	ENSP00000333984.5	Q13061-1
	TRDN	ENST00000628709.2	TSL:1	c.793+61T>C		intron	N/A	ENSP00000486095.1	Q13061-2

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 249 AN: 152014 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00585

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000386 AC: 92 AN: 238140 AF XY: 0.000279

Gnomad AFR exome AF: 0.00515

Gnomad AMR exome AF: 0.000392

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000935

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000197 AC: 287 AN: 1454248 Hom.: 2 Cov.: 32 AF XY: 0.000185 AC XY: 134 AN XY: 722848

African (AFR) AF: 0.00637 AC: 212 AN: 33282

American (AMR) AF: 0.000505 AC: 22 AN: 43584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25956

East Asian (EAS) AF: 0.00 AC: 0 AN: 39562

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52328

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5752

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1108864

Other (OTH) AF: 0.000382 AC: 23 AN: 60144

GnomAD4 genome AF: 0.00163 AC: 248 AN: 152132 Hom.: 0 Cov.: 31 AF XY: 0.00171 AC XY: 127 AN XY: 74368

African (AFR) AF: 0.00580 AC: 241 AN: 41520

American (AMR) AF: 0.000327 AC: 5 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67976

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00262 Hom.: 0

Bravo AF: 0.00195

ExAC AF: 0.000489 AC: 59

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 5 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	6.0
DANN	Benign	0.55
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.0062	T
PhyloP100		-0.24
Sift4G	Benign	0.13	T
Vest4		0.26
MVP		0.28
GERP RS		-1.4
Mutation Taster		=100/0	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: rs572614305; hg19: chr6-123824803;