3-52452236-G-C

Position:

• chr3-52452236-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1 PP3_Strong BS2

The ENST00000232975.8(TNNC1):​c.72C>G​(p.Phe24Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,460,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F24F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: TNNC1 ENST00000232975.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0650

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 domain EF-hand 1 (size 35) in uniprot entity TNNC1_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in ENST00000232975.8
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNC1	NM_003280.3	c.72C>G	p.Phe24Leu	missense_variant	3/6	ENST00000232975.8	NP_003271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNC1	ENST00000232975.8	c.72C>G	p.Phe24Leu	missense_variant	3/6	1	NM_003280.3	ENSP00000232975	P1
TNNC1	ENST00000496590.1	c.-61C>G		5_prime_UTR_variant	2/4	2		ENSP00000420596

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1460522 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726590

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.96
MutPred		0.68		Loss of ubiquitination at K21 (P = 0.1351);
MVP		1.0
MPC		3.7
ClinPred		1.0	D
GERP RS		-4.5
Varity_R		0.99
gMVP		1.0

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

Other links and lift over

dbSNP: rs751682878; hg19: chr3-52486252;