chr6-123377897-T-G

Variant names:

• chr6-123377897-T-G
• rs6901953
• NM_006073.4:c.1188A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006073.4(TRDN):​c.1188A>C​(p.Lys396Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. K396E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRDN NM_006073.4 missense, splice_region
• Scores: Splicing: ADA: 0.1355
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.10
• 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 Gene-Disease associations (from GenCC):

• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• catecholaminergic polymorphic ventricular tachycardia 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• familial long QT syndrome

  Inheritance: AR Classification: STRONG Submitted by: G2P
• long QT syndrome

  Inheritance: AR Classification: STRONG Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0842337).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRDN	NM_006073.4	c.1188A>C	p.Lys396Asn	missense_variant, splice_region_variant	Exon 17 of 41	ENST00000334268.9	NP_006064.2
TRDN	NM_001251987.2	c.1191A>C	p.Lys397Asn	missense_variant, splice_region_variant	Exon 17 of 21		NP_001238916.1
TRDN	NM_001407315.1	c.1131A>C	p.Lys377Asn	missense_variant, splice_region_variant	Exon 16 of 20		NP_001394244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9	c.1188A>C	p.Lys396Asn	missense_variant, splice_region_variant	Exon 17 of 41	1	NM_006073.4	ENSP00000333984.5
TRDN	ENST00000662930.1	c.1191A>C	p.Lys397Asn	missense_variant, splice_region_variant	Exon 17 of 21			ENSP00000499585.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1

Aug 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 396 of the TRDN protein (p.Lys396Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TRDN-related conditions. ClinVar contains an entry for this variant (Variation ID: 1052434). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PhyloP100		1.1
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.021
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.059	T
Polyphen		0.053	B
Vest4		0.27
MutPred		0.22		Loss of methylation at K396 (P = 0.0029);
MVP		0.17
ClinPred		0.85	D
GERP RS		3.8
Varity_R		0.21
gMVP		0.0059
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.14
dbscSNV1_RF	Benign	0.43
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: rs6901953; hg19: chr6-123699042;