rs77768246

Variant names:

• chr6-123439007-G-C
• rs77768246
• NM_006073.4:c.932-4C>G

Your query was ambiguous. Multiple possible variants found:

• chr6-123439007-G-C
• chr6-123439007-G-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The ENST00000334268.9(TRDN):​c.932-4C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,544,922 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (45 hom.)
• Consequence: TRDN ENST00000334268.9 splice_region, intron
• Scores: Splicing: ADA: 0.001468
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.268
• Publications: 2 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 6-123439007-G-C is Benign according to our data. Variant chr6-123439007-G-C is described in ClinVar as Benign. ClinVar VariationId is 227124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00155 (236/152010) while in subpopulation EAS AF = 0.0412 (213/5164). AF 95% confidence interval is 0.0367. There are 7 homozygotes in GnomAd4. There are 132 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000334268.9. 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.932-4C>G		splice_region intron	N/A	NP_006064.2
	TRDN	NM_001251987.2		c.932-4C>G		splice_region intron	N/A	NP_001238916.1
	TRDN	NM_001407315.1		c.872-4C>G		splice_region intron	N/A	NP_001394244.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRDN	ENST00000334268.9	TSL:1 MANE Select	c.932-4C>G		splice_region intron	N/A	ENSP00000333984.5
	TRDN	ENST00000662930.1		c.932-4C>G		splice_region intron	N/A	ENSP00000499585.1
	TRDN-AS1	ENST00000587106.6	TSL:5	n.572-596G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 237 AN: 151892 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0413

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00298 AC: 479 AN: 160620 AF XY: 0.00276

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0368

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000768

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00143 AC: 1991 AN: 1392912 Hom.: 45 Cov.: 28 AF XY: 0.00141 AC XY: 972 AN XY: 687974

African (AFR) AF: 0.00 AC: 0 AN: 31450

American (AMR) AF: 0.00 AC: 0 AN: 34646

Ashkenazi Jewish (ASJ) AF: 0.0000403 AC: 1 AN: 24824

East Asian (EAS) AF: 0.0460 AC: 1703 AN: 37060

South Asian (SAS) AF: 0.00149 AC: 115 AN: 77390

European-Finnish (FIN) AF: 0.0000203 AC: 1 AN: 49224

Middle Eastern (MID) AF: 0.000355 AC: 2 AN: 5638

European-Non Finnish (NFE) AF: 0.0000400 AC: 43 AN: 1074964

Other (OTH) AF: 0.00218 AC: 126 AN: 57716

GnomAD4 genome AF: 0.00155 AC: 236 AN: 152010 Hom.: 7 Cov.: 32 AF XY: 0.00178 AC XY: 132 AN XY: 74288

African (AFR) AF: 0.0000482 AC: 2 AN: 41462

American (AMR) AF: 0.000197 AC: 3 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0412 AC: 213 AN: 5164

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67978

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.000291 Hom.: 0

Bravo AF: 0.00181

Asia WGS AF: 0.0260 AC: 91 AN: 3472

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	8.9
DANN	Benign	0.72
PhyloP100		0.27
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0015
dbscSNV1_RF	Benign	0.15
SpliceAI score (max)		0.060		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: rs77768246; hg19: chr6-123760152; COSMIC: COSV62116220; COSMIC: COSV62116220;