chr20-45824594-C-A

Position:

• chr20-45824594-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS1_Moderate PM1 PM2 PP5

The NM_003279.3(TNNC2):​c.100G>T​(p.Asp34Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNNC2 NM_003279.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.11

Genes affected

TNNC2 (HGNC:11944): (troponin C2, fast skeletal type) Troponin (Tn), a key protein complex in the regulation of striated muscle contraction, is composed of 3 subunits. The Tn-I subunit inhibits actomyosin ATPase, the Tn-T subunit binds tropomyosin and Tn-C, while the Tn-C subunit binds calcium and overcomes the inhibitory action of the troponin complex on actin filaments. The protein encoded by this gene is the Tn-C subunit. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PS1: Transcript NM_003279.3 (TNNC2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a chain Troponin C, skeletal muscle (size 158) in uniprot entity TNNC2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_003279.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-45824594-C-A is Pathogenic according to our data. Variant chr20-45824594-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1806474.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNC2	NM_003279.3	c.100G>T	p.Asp34Tyr	missense_variant	3/6	ENST00000372555.8
TNNC2	XM_011529031.3	c.55G>T	p.Asp19Tyr	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNC2	ENST00000372555.8	c.100G>T	p.Asp34Tyr	missense_variant	3/6	1	NM_003279.3	P1
TNNC2	ENST00000372557.1	c.55G>T	p.Asp19Tyr	missense_variant	4/7	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Congenital myopathy 15 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 16, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Uncertain	-0.015	T
MutationAssessor	Benign	-0.96	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.0	N;N
REVEL	Uncertain	0.45
Sift	Uncertain	0.021	D;D
Sift4G	Benign	0.37	T;T
Polyphen		1.0	D;.
Vest4		0.68
MutPred		0.28		Loss of disorder (P = 0.0222);.;
MVP		0.72
MPC		2.1
ClinPred		0.95	D
GERP RS		4.5
Varity_R		0.42
gMVP		0.93

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-44453233;