Genetic Variant TNNC2:p.Thr128Thr (chr20-45824058-C-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP7BA1

The NM_003279.3(TNNC2):c.384G>T(p.Thr128Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.518 in 1,613,748 control chromosomes in the GnomAD database, including 222,323 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.45 ( 16722 hom., cov: 31)

Exomes 𝑓: 0.53 ( 205601 hom. )

Consequence

TNNC2
NM_003279.3 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.65

Publications

36 publications found

Variant links:

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]

TNNC2 Gene-Disease associations (from GenCC):

congenital myopathy 15
Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
hypertrophic cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

TNNC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.4).

BP7

Synonymous conserved (PhyloP=-4.65 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.539 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNC2	NM_003279.3 link	c.384G>T	p.Thr128Thr	synonymous_variant	Exon 5 of 6	ENST00000372555.8	NP_003270.1	P02585
TNNC2	XM_011529031.3 link	c.339G>T	p.Thr113Thr	synonymous_variant	Exon 5 of 6		XP_011527333.1	C9J7T9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNC2	ENST00000372555.8 link	c.384G>T	p.Thr128Thr	synonymous_variant	Exon 5 of 6	1	NM_003279.3	ENSP00000361636.3		P02585
TNNC2	ENST00000372557.1 link	c.339G>T	p.Thr113Thr	synonymous_variant	Exon 6 of 7	3		ENSP00000361638.1		C9J7T9

Frequencies

GnomAD3 genomes

AF:

0.449

AC:

68167

AN:

151904

Hom.:

16710

Cov.:

show subpopulations

Gnomad AFR

AF:

0.244

Gnomad AMI

AF:

0.566

Gnomad AMR

AF:

0.499

Gnomad ASJ

AF:

0.395

Gnomad EAS

AF:

0.529

Gnomad SAS

AF:

0.365

Gnomad FIN

AF:

0.576

Gnomad MID

AF:

0.468

Gnomad NFE

AF:

0.543

Gnomad OTH

AF:

0.452

GnomAD2 exomes

AF:

0.503

AC:

126328

AN:

251366

AF XY:

0.497

show subpopulations

Gnomad AFR exome

AF:

0.236

Gnomad AMR exome

AF:

0.590

Gnomad ASJ exome

AF:

0.388

Gnomad EAS exome

AF:

0.524

Gnomad FIN exome

AF:

0.570

Gnomad NFE exome

AF:

0.545

Gnomad OTH exome

AF:

0.505

GnomAD4 exome

AF:

0.526

AC:

768409

AN:

1461726

Hom.:

205601

Cov.:

AF XY:

0.521

AC XY:

378788

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.235

AC:

7867

AN:

33480

American (AMR)

AF:

0.580

AC:

25914

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.388

AC:

10150

AN:

26132

East Asian (EAS)

AF:

0.559

AC:

22183

AN:

39696

South Asian (SAS)

AF:

0.372

AC:

32046

AN:

86254

European-Finnish (FIN)

AF:

0.577

AC:

30778

AN:

53374

Middle Eastern (MID)

AF:

0.428

AC:

2467

AN:

5768

European-Non Finnish (NFE)

AF:

0.546

AC:

607442

AN:

1111916

Other (OTH)

AF:

0.490

AC:

29562

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

20540

41080

61620

82160

102700

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16976

33952

50928

67904

84880

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.449

AC:

68195

AN:

152022

Hom.:

16722

Cov.:

AF XY:

0.449

AC XY:

33346

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.244

AC:

10128

AN:

41488

American (AMR)

AF:

0.499

AC:

7630

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.395

AC:

1369

AN:

3470

East Asian (EAS)

AF:

0.528

AC:

2725

AN:

5158

South Asian (SAS)

AF:

0.368

AC:

1775

AN:

4820

European-Finnish (FIN)

AF:

0.576

AC:

6080

AN:

10556

Middle Eastern (MID)

AF:

0.459

AC:

135

AN:

294

European-Non Finnish (NFE)

AF:

0.543

AC:

36897

AN:

67932

Other (OTH)

AF:

0.445

AC:

940

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1818

3636

5454

7272

9090

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

624

1248

1872

2496

3120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.510

Hom.:

36578

Bravo

AF:

0.439

Asia WGS

AF:

0.414

AC:

1440

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

0.70

(source)

DANN

Benign

0.92

PhyloP100

-4.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over