3-52451278-C-A

Variant names:

• chr3-52451278-C-A
• NM_003280.3:c.483G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_003280.3(TNNC1):​c.483G>T​(p.Glu161Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TNNC1 NM_003280.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.251

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a chain Troponin C, slow skeletal and cardiac muscles (size 160) in uniprot entity TNNC1_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) in NM_003280.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12060365).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNC1	NM_003280.3	c.483G>T	p.Glu161Asp	missense_variant	Exon 6 of 6	ENST00000232975.8	NP_003271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNC1	ENST00000232975.8	c.483G>T	p.Glu161Asp	missense_variant	Exon 6 of 6	1	NM_003280.3	ENSP00000232975.3
TNNC1	ENST00000496590.1	c.*137G>T		downstream_gene_variant		2		ENSP00000420596.1
TNNC1	ENST00000461086.1	n.*161G>T		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dilated cardiomyopathy 1Z;C2750472:Hypertrophic cardiomyopathy 13 Uncertain:1

Aug 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 161 of the TNNC1 protein (p.Glu161Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TNNC1-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.35	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.0	L
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.22
Sift	Benign	0.049	D
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.34
MutPred		0.39		Gain of stability (P = 0.0167);
MVP		0.36
MPC		0.47
ClinPred		0.85	D
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.50
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-52485294;