Variant chr3-52451410-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_003280.3(TNNC1):c.435C>G(p.Asp145Glu) 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 pathogenic 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. D145N) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

TNNC1
NM_003280.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.766

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 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 chr3-52451412-C-T is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.981

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNC1	NM_003280.3 link	c.435C>G	p.Asp145Glu	missense_variant	5/6	ENST00000232975.8	NP_003271.1	P63316Q6FH91

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TNNC1	ENST00000232975.8 link	c.435C>G	p.Asp145Glu	missense_variant	5/6	1	NM_003280.3	ENSP00000232975.3	P63316
TNNC1	ENST00000496590.1 link	c.*5C>G		downstream_gene_variant		2		ENSP00000420596.1	C9JDI3
TNNC1	ENST00000461086.1 link	n.*29C>G		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250846

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135780

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Benign

5.8

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.77

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.51

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.10

MutationAssessor

Uncertain

2.8

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.0

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.020

Polyphen

0.93

Vest4

0.85

MutPred

0.89

Gain of solvent accessibility (P = 0.1014);

MVP

0.95

MPC

1.4

ClinPred

0.95

GERP RS

-3.0

Varity_R

0.87

gMVP

0.81

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over