rs751682878

Variant names:

• chr3-52452236-G-A
• rs751682878
• NM_003280.3:c.72C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-52452236-G-A
• chr3-52452236-G-C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_003280.3(TNNC1):​c.72C>T​(p.Phe24Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000466 in 1,460,522 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: not found (cov: 33)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: TNNC1 NM_003280.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0650
• Publications: 0 publications found

Genes affected

TNNC1 (HGNC:11943): (troponin C1, slow skeletal and cardiac type) Troponin is a central regulatory protein of striated muscle contraction, and together with tropomyosin, is located on the actin filament. Troponin consists of 3 subunits: TnI, which is the inhibitor of actomyosin ATPase; TnT, which contains the binding site for tropomyosin; and TnC, the protein encoded by this gene. The binding of calcium to TnC abolishes the inhibitory action of TnI, thus allowing the interaction of actin with myosin, the hydrolysis of ATP, and the generation of tension. Mutations in this gene are associated with cardiomyopathy dilated type 1Z. [provided by RefSeq, Oct 2008]

TNNC1 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1Z

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 13

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 3-52452236-G-A is Benign according to our data. Variant chr3-52452236-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 239536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.065 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000466 (68/1460522) while in subpopulation NFE AF = 0.0000558 (62/1112002). AF 95% confidence interval is 0.0000444. There are 0 homozygotes in GnomAdExome4. There are 33 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 68 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003280.3. 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
	TNNC1	NM_003280.3	MANE Select	c.72C>T	p.Phe24Phe	synonymous	Exon 3 of 6	NP_003271.1	P63316

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNC1	ENST00000232975.8	TSL:1 MANE Select	c.72C>T	p.Phe24Phe	synonymous	Exon 3 of 6	ENSP00000232975.3	P63316
	TNNC1	ENST00000496590.1	TSL:2	c.-61C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	ENSP00000420596.1	C9JDI3
	TNNC1	ENST00000496590.1	TSL:2	c.-61C>T		5_prime_UTR	Exon 2 of 4	ENSP00000420596.1	C9JDI3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000280 AC: 7 AN: 250338 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000466 AC: 68 AN: 1460522 Hom.: 0 Cov.: 31 AF XY: 0.0000454 AC XY: 33 AN XY: 726590

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000558 AC: 62 AN: 1112002

Other (OTH) AF: 0.0000166 AC: 1 AN: 60378

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000882 Hom.: 0

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1Z;C2750472:Hypertrophic cardiomyopathy 13 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	10
DANN	Benign	0.81
PhyloP100		-0.065
Mutation Taster		=94/6	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: rs751682878; hg19: chr3-52486252; COSMIC: COSV51767963; COSMIC: COSV51767963;