rs376370234

Variant names:

• chr6-123438079-A-G
• rs376370234
• NM_006073.4:c.1035T>C

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.1035T>C​(p.Ile345Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000451 in 1,595,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: TRDN NM_006073.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0190
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 6-123438079-A-G is Benign according to our data. Variant chr6-123438079-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 392340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.019 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRDN	NM_006073.4	MANE Select	c.1035T>C	p.Ile345Ile	synonymous	Exon 12 of 41	NP_006064.2	Q13061-1
	TRDN	NM_001251987.2		c.1038T>C	p.Ile346Ile	synonymous	Exon 12 of 21	NP_001238916.1	A0A590UJV0
	TRDN	NM_001407315.1		c.978T>C	p.Ile326Ile	synonymous	Exon 11 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.1035T>C	p.Ile345Ile	synonymous	Exon 12 of 41	ENSP00000333984.5	Q13061-1
	TRDN	ENST00000962661.1		c.1038T>C	p.Ile346Ile	synonymous	Exon 12 of 41	ENSP00000632720.1
	TRDN	ENST00000962654.1		c.1038T>C	p.Ile346Ile	synonymous	Exon 12 of 41	ENSP00000632713.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000133 AC: 3 AN: 226160 AF XY: 0.00000818

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: 0.0000289

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000450 AC: 65 AN: 1443396 Hom.: 0 Cov.: 30 AF XY: 0.0000488 AC XY: 35 AN XY: 716908

African (AFR) AF: 0.0000309 AC: 1 AN: 32336

American (AMR) AF: 0.00 AC: 0 AN: 40496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25608

East Asian (EAS) AF: 0.00 AC: 0 AN: 39380

South Asian (SAS) AF: 0.00 AC: 0 AN: 82110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52708

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.0000552 AC: 61 AN: 1105404

Other (OTH) AF: 0.0000503 AC: 3 AN: 59670

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152082 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74290

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

African (AFR) AF: 0.00 AC: 0 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000545952), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000283 Hom.: 0

ClinVar

ClinVar submissions

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.0
DANN	Benign	0.74
PhyloP100		0.019

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs376370234; hg19: chr6-123759224;