6-123273009-G-C

Variant names:

• chr6-123273009-G-C
• rs9398723
• NM_006073.4:c.1627C>G

Variant summary

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

The NM_006073.4(TRDN):​c.1627C>G​(p.Gln543Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000742 in 1,348,148 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q543K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: TRDN NM_006073.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• 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: 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1627C>G	p.Gln543Glu	missense splice_region	Exon 29 of 41	NP_006064.2	Q13061-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRDN	ENST00000334268.9	TSL:1 MANE Select	c.1627C>G	p.Gln543Glu	missense splice_region	Exon 29 of 41	ENSP00000333984.5	Q13061-1
	TRDN	ENST00000962661.1		c.1630C>G	p.Gln544Glu	missense splice_region	Exon 29 of 41	ENSP00000632720.1
	TRDN	ENST00000962654.1		c.1627C>G	p.Gln543Glu	missense splice_region	Exon 29 of 41	ENSP00000632713.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.42e-7 AC: 1 AN: 1348148 Hom.: 0 Cov.: 27 AF XY: 0.00000150 AC XY: 1 AN XY: 664986

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

African (AFR) AF: 0.00 AC: 0 AN: 28184

American (AMR) AF: 0.00 AC: 0 AN: 22216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23208

East Asian (EAS) AF: 0.00 AC: 0 AN: 34658

South Asian (SAS) AF: 0.00 AC: 0 AN: 70304

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48846

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5482

European-Non Finnish (NFE) AF: 9.44e-7 AC: 1 AN: 1059456

Other (OTH) AF: 0.00 AC: 0 AN: 55794

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.97	L
PhyloP100		1.1
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.090	N
REVEL	Benign	0.028
Sift	Pathogenic	0.0	D
Sift4G	Benign	1.0	T
Polyphen		0.0050	B
Vest4		0.12
MutPred		0.40		Loss of MoRF binding (P = 0.0274)
MVP		0.099
ClinPred		0.16	T
GERP RS		1.9
Varity_R		0.18
gMVP		0.0047
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: -1

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

Other links and lift over

dbSNP: rs9398723; hg19: chr6-123594154;