Genetic Variant TNNC2:c.-42-2586A>G (chr20-45827420-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000372557.1(TNNC2):c.-42-2586A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.515 in 742,138 control chromosomes in the GnomAD database, including 101,652 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 0.46 ( 16983 hom., cov: 29)

Exomes 𝑓: 0.53 ( 84669 hom. )

Consequence

TNNC2
ENST00000372557.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.274

Publications

6 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.54 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNC2	XM_011529031.3 link	c.-42-2586A>G		intron_variant	Intron 1 of 5		XP_011527333.1
TNNC2	NM_003279.3 link	c.-172A>G		upstream_gene_variant		ENST00000372555.8	NP_003270.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNC2	ENST00000372557.1 link	c.-42-2586A>G		intron_variant	Intron 2 of 6	3		ENSP00000361638.1
TNNC2	ENST00000372555.8 link	c.-172A>G		upstream_gene_variant		1	NM_003279.3	ENSP00000361636.3

Frequencies

GnomAD3 genomes

AF:

0.458

AC:

69016

AN:

150694

Hom.:

16962

Cov.:

show subpopulations

Gnomad AFR

AF:

0.270

Gnomad AMI

AF:

0.565

Gnomad AMR

AF:

0.501

Gnomad ASJ

AF:

0.399

Gnomad EAS

AF:

0.528

Gnomad SAS

AF:

0.378

Gnomad FIN

AF:

0.580

Gnomad MID

AF:

0.478

Gnomad NFE

AF:

0.545

Gnomad OTH

AF:

0.463

GnomAD4 exome

AF:

0.530

AC:

313161

AN:

591328

Hom.:

84669

AF XY:

0.522

AC XY:

159642

AN XY:

305692

show subpopulations

African (AFR)

AF:

0.268

AC:

4142

AN:

15436

American (AMR)

AF:

0.566

AC:

14675

AN:

25936

Ashkenazi Jewish (ASJ)

AF:

0.397

AC:

6236

AN:

15700

East Asian (EAS)

AF:

0.572

AC:

17998

AN:

31478

South Asian (SAS)

AF:

0.383

AC:

20049

AN:

52384

European-Finnish (FIN)

AF:

0.583

AC:

21155

AN:

36288

Middle Eastern (MID)

AF:

0.454

AC:

1614

AN:

3558

European-Non Finnish (NFE)

AF:

0.558

AC:

212021

AN:

379734

Other (OTH)

AF:

0.496

AC:

15271

AN:

30814

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

7166

14333

21499

28666

35832

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3088

6176

9264

12352

15440

<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:

0.458

AC:

69058

AN:

150810

Hom.:

16983

Cov.:

AF XY:

0.458

AC XY:

33695

AN XY:

73560

show subpopulations

African (AFR)

AF:

0.270

AC:

11061

AN:

40950

American (AMR)

AF:

0.502

AC:

7615

AN:

15182

Ashkenazi Jewish (ASJ)

AF:

0.399

AC:

1383

AN:

3464

East Asian (EAS)

AF:

0.528

AC:

2660

AN:

5042

South Asian (SAS)

AF:

0.380

AC:

1807

AN:

4754

European-Finnish (FIN)

AF:

0.580

AC:

6010

AN:

10364

Middle Eastern (MID)

AF:

0.466

AC:

137

AN:

294

European-Non Finnish (NFE)

AF:

0.545

AC:

36921

AN:

67768

Other (OTH)

AF:

0.456

AC:

952

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1754

3508

5262

7016

8770

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

634

1268

1902

2536

3170

<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:

0.454

Hom.:

2724

Bravo

AF:

0.449

Asia WGS

AF:

0.423

AC:

1472

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

(source)

DANN

Benign

0.69

PhyloP100

0.27

PromoterAI

0.032

Neutral

(source)

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

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