rs377440434

Variant names:

• chr6-123548470-G-A
• rs377440434
• NM_006073.4:c.375C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-123548470-G-A
• chr6-123548470-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_006073.4(TRDN):​c.375C>T​(p.Asp125Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00033 in 1,562,774 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00034 (1 hom.)
• Consequence: TRDN NM_006073.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.13
• Publications: 1 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

ENSG00000285691 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 6-123548470-G-A is Benign according to our data. Variant chr6-123548470-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 264376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.13 with no splicing effect.

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.375C>T	p.Asp125Asp	synonymous	Exon 3 of 41	NP_006064.2
	TRDN	NM_001251987.2		c.375C>T	p.Asp125Asp	synonymous	Exon 3 of 21	NP_001238916.1
	TRDN	NM_001407315.1		c.375C>T	p.Asp125Asp	synonymous	Exon 3 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.375C>T	p.Asp125Asp	synonymous	Exon 3 of 41	ENSP00000333984.5
	TRDN	ENST00000628709.2	TSL:1	c.375C>T	p.Asp125Asp	synonymous	Exon 3 of 9	ENSP00000486095.1
	TRDN	ENST00000546248.6	TSL:1	c.375C>T	p.Asp125Asp	synonymous	Exon 3 of 8	ENSP00000439281.2

Frequencies

GnomAD3 genomes AF: 0.000211 AC: 32 AN: 151368 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000728

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000264

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000418

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000339

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000205 AC: 41 AN: 200084 AF XY: 0.000231

Gnomad AFR exome AF: 0.000243

Gnomad AMR exome AF: 0.000115

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000507

Gnomad NFE exome AF: 0.000254

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000342 AC: 483 AN: 1411288 Hom.: 1 Cov.: 35 AF XY: 0.000375 AC XY: 262 AN XY: 699574

African (AFR) AF: 0.0000954 AC: 3 AN: 31434

American (AMR) AF: 0.000323 AC: 12 AN: 37102

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24440

East Asian (EAS) AF: 0.0000519 AC: 2 AN: 38514

South Asian (SAS) AF: 0.000482 AC: 37 AN: 76782

European-Finnish (FIN) AF: 0.0000195 AC: 1 AN: 51386

Middle Eastern (MID) AF: 0.000179 AC: 1 AN: 5582

European-Non Finnish (NFE) AF: 0.000379 AC: 412 AN: 1087920

Other (OTH) AF: 0.000258 AC: 15 AN: 58128

GnomAD4 genome AF: 0.000211 AC: 32 AN: 151486 Hom.: 0 Cov.: 31 AF XY: 0.000149 AC XY: 11 AN XY: 73986

African (AFR) AF: 0.0000726 AC: 3 AN: 41336

American (AMR) AF: 0.000263 AC: 4 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000419 AC: 2 AN: 4776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10472

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000339 AC: 23 AN: 67780

Other (OTH) AF: 0.00 AC: 0 AN: 2100

Alfa AF: 0.000176 Hom.: 0

Bravo AF: 0.000212

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.012
DANN	Benign	0.22
PhyloP100		-3.1
Mutation Taster		=99/1	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: rs377440434; hg19: chr6-123869615; COSMIC: COSV100520632;