rs758037868

Variant names:

• chr6-123503847-A-C
• rs758037868
• NM_006073.4:c.665T>G

Your query was ambiguous. Multiple possible variants found:

• chr6-123503847-A-C
• chr6-123503847-A-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_006073.4(TRDN):​c.665T>G​(p.Val222Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000969 in 1,445,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. V222M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000097 (0 hom.)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.16
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14888501).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRDN	NM_006073.4	MANE Select	c.665T>G	p.Val222Gly	missense	Exon 8 of 41	NP_006064.2
	TRDN	NM_001251987.2		c.665T>G	p.Val222Gly	missense	Exon 8 of 21	NP_001238916.1
	TRDN	NM_001407315.1		c.665T>G	p.Val222Gly	missense	Exon 8 of 20	NP_001394244.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRDN	ENST00000334268.9	TSL:1 MANE Select	c.665T>G	p.Val222Gly	missense	Exon 8 of 41	ENSP00000333984.5
	TRDN	ENST00000628709.2	TSL:1	c.665T>G	p.Val222Gly	missense	Exon 8 of 9	ENSP00000486095.1
	TRDN	ENST00000546248.6	TSL:1	c.665T>G	p.Val222Gly	missense	Exon 8 of 8	ENSP00000439281.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000913 AC: 2 AN: 218958 AF XY: 0.00000847

Gnomad AFR exome AF: 0.00

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: 0.0000210

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000969 AC: 14 AN: 1445500 Hom.: 0 Cov.: 32 AF XY: 0.00000976 AC XY: 7 AN XY: 717578

African (AFR) AF: 0.00 AC: 0 AN: 33378

American (AMR) AF: 0.00 AC: 0 AN: 41522

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25786

East Asian (EAS) AF: 0.00 AC: 0 AN: 39330

South Asian (SAS) AF: 0.00 AC: 0 AN: 84602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52538

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.0000127 AC: 14 AN: 1102800

Other (OTH) AF: 0.00 AC: 0 AN: 59806

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000834 AC: 1

ClinVar

ClinVar submissions as Germline

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.078
Eigen_PC	Benign	-0.065
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.2
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.063
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.0070	B
Vest4		0.24
MutPred		0.35		Gain of relative solvent accessibility (P = 0.005)
MVP		0.58
ClinPred		0.24	T
GERP RS		1.9
Varity_R		0.46
gMVP		0.015
Mutation Taster		=71/29	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: rs758037868; hg19: chr6-123824992;