6-123393674-G-T

Variant names:

• chr6-123393674-G-T
• rs754708708
• NM_006073.4:c.1055C>A

Variant summary

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

The NM_006073.4(TRDN):​c.1055C>A​(p.Pro352Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,604,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P352L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.63
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.1055C>A	p.Pro352Gln	missense	Exon 13 of 41	NP_006064.2	Q13061-1
	TRDN	NM_001251987.2		c.1058C>A	p.Pro353Gln	missense	Exon 13 of 21	NP_001238916.1	A0A590UJV0
	TRDN	NM_001407315.1		c.998C>A	p.Pro333Gln	missense	Exon 12 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.1055C>A	p.Pro352Gln	missense	Exon 13 of 41	ENSP00000333984.5	Q13061-1
	TRDN	ENST00000962661.1		c.1058C>A	p.Pro353Gln	missense	Exon 13 of 41	ENSP00000632720.1
	TRDN	ENST00000962654.1		c.1058C>A	p.Pro353Gln	missense	Exon 13 of 41	ENSP00000632713.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 151764 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000387

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000478

GnomAD2 exomes AF: 0.00000850 AC: 2 AN: 235388 AF XY: 0.00000783

Gnomad AFR exome AF: 0.000141

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000689 AC: 10 AN: 1452378 Hom.: 0 Cov.: 30 AF XY: 0.00000554 AC XY: 4 AN XY: 721854

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

African (AFR) AF: 0.000270 AC: 9 AN: 33294

American (AMR) AF: 0.00 AC: 0 AN: 43730

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25798

East Asian (EAS) AF: 0.00 AC: 0 AN: 39538

South Asian (SAS) AF: 0.00 AC: 0 AN: 84934

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106562

Other (OTH) AF: 0.0000167 AC: 1 AN: 59936

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000599527), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000112 AC: 17 AN: 151764 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74108

African (AFR) AF: 0.000387 AC: 16 AN: 41308

American (AMR) AF: 0.00 AC: 0 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67920

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.0000387 Hom.: 0

Bravo AF: 0.000132

ExAC AF: 0.00000829 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		2.6
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.097
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.34	T
Polyphen		0.96	P
Vest4		0.39
MVP		0.31
ClinPred		0.32	T
GERP RS		2.3
Varity_R		0.066
gMVP		0.019
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.49		Position offset: -2

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

Other links and lift over

dbSNP: rs754708708; hg19: chr6-123714819;