6-123548571-C-T

Variant names:

• chr6-123548571-C-T
• rs34808221
• NM_006073.4:c.274G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006073.4(TRDN):​c.274G>A​(p.Val92Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,555,512 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V92L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0066 (15 hom., cov: 31)
  • Exomes 𝑓: 0.00063 (13 hom.)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.19
• Publications: 4 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

ENSG00000285691 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003935635).
• BP6: Variant 6-123548571-C-T is Benign according to our data. Variant chr6-123548571-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227118.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 = 0.00664 (1002/150856) while in subpopulation AFR AF = 0.0226 (929/41044). AF 95% confidence interval is 0.0214. There are 15 homozygotes in GnomAd4. There are 460 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AD,AR gene

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.274G>A	p.Val92Ile	missense	Exon 3 of 41	NP_006064.2	Q13061-1
	TRDN	NM_001251987.2		c.274G>A	p.Val92Ile	missense	Exon 3 of 21	NP_001238916.1	A0A590UJV0
	TRDN	NM_001407315.1		c.274G>A	p.Val92Ile	missense	Exon 3 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.274G>A	p.Val92Ile	missense	Exon 3 of 41	ENSP00000333984.5	Q13061-1
	TRDN	ENST00000628709.2	TSL:1	c.274G>A	p.Val92Ile	missense	Exon 3 of 9	ENSP00000486095.1	Q13061-2
	TRDN	ENST00000546248.6	TSL:1	c.274G>A	p.Val92Ile	missense	Exon 3 of 8	ENSP00000439281.2	H9ME53

Frequencies

GnomAD3 genomes AF: 0.00661 AC: 997 AN: 150740 Hom.: 14 Cov.: 31

Gnomad AFR AF: 0.0226

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00358

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: 0.000118

Gnomad OTH AF: 0.00532

GnomAD2 exomes AF: 0.00155 AC: 289 AN: 186128 AF XY: 0.00118

Gnomad AFR exome AF: 0.0232

Gnomad AMR exome AF: 0.000993

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000371

Gnomad OTH exome AF: 0.00108

GnomAD4 exome AF: 0.000633 AC: 889 AN: 1404656 Hom.: 13 Cov.: 35 AF XY: 0.000537 AC XY: 373 AN XY: 695136

African (AFR) AF: 0.0229 AC: 726 AN: 31770

American (AMR) AF: 0.00153 AC: 57 AN: 37332

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24890

East Asian (EAS) AF: 0.00 AC: 0 AN: 37502

South Asian (SAS) AF: 0.0000781 AC: 6 AN: 76816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50854

Middle Eastern (MID) AF: 0.00213 AC: 12 AN: 5632

European-Non Finnish (NFE) AF: 0.00000832 AC: 9 AN: 1081856

Other (OTH) AF: 0.00136 AC: 79 AN: 58004

GnomAD4 genome AF: 0.00664 AC: 1002 AN: 150856 Hom.: 15 Cov.: 31 AF XY: 0.00625 AC XY: 460 AN XY: 73580

African (AFR) AF: 0.0226 AC: 929 AN: 41044

American (AMR) AF: 0.00358 AC: 54 AN: 15098

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67758

Other (OTH) AF: 0.00526 AC: 11 AN: 2090

Alfa AF: 0.00250 Hom.: 8

Bravo AF: 0.00765

ESP6500AA AF: 0.0229 AC: 84

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.00170 AC: 204

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	0.051
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.2
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.055
Sift	Benign	0.17	T
Sift4G	Benign	0.58	T
Polyphen		0.78	P
Vest4		0.086
MVP		0.17
ClinPred		0.0087	T
GERP RS		4.4
Varity_R		0.053
gMVP		0.13
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs34808221; hg19: chr6-123869716;