rs104893823

Variant names:

• chr3-52451285-C-G
• NM_003280.3:c.476G>C

Your query was ambiguous. Multiple possible variants found:

• chr3-52451285-C-G
• chr3-52451285-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1 PM2 PM5 BP4

The NM_003280.3(TNNC1):​c.476G>C​(p.Gly159Ala) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G159D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TNNC1 NM_003280.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.02

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 5 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-52451285-C-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.29801506).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNC1	NM_003280.3	c.476G>C	p.Gly159Ala	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.476G>C	p.Gly159Ala	missense_variant	Exon 6 of 6	1	NM_003280.3	ENSP00000232975.3
TNNC1	ENST00000496590.1	c.*130G>C		downstream_gene_variant		2		ENSP00000420596.1
TNNC1	ENST00000461086.1	n.*154G>C		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.30	T
MetaSVM	Uncertain	0.48	D
MutationAssessor	Benign	0.74	N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.17	N
REVEL	Uncertain	0.39
Sift	Benign	0.28	T
Sift4G	Uncertain	0.033	D
Polyphen		0.99	D
Vest4		0.15
MutPred		0.49		Loss of disorder (P = 0.086);
MVP		0.71
MPC		1.5
ClinPred		0.87	D
GERP RS		5.2
Varity_R		0.48
gMVP		0.81

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: chr3-52485301;