3-52451192-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003280.3(TNNC1):c.*83A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00263 in 1,557,348 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 36 hom., cov: 33)

Exomes 𝑓: 0.0016 ( 34 hom. )

Consequence

TNNC1
NM_003280.3 3_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.867

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 3-52451192-T-G is Benign according to our data. Variant chr3-52451192-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 346129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0119 (1814/152244) while in subpopulation AFR AF= 0.0393 (1631/41540). AF 95% confidence interval is 0.0377. There are 36 homozygotes in gnomad4. There are 824 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd at 1808 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNC1	NM_003280.3 linkuse as main transcript	c.*83A>C		3_prime_UTR_variant	6/6	ENST00000232975.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNC1	ENST00000232975.8 linkuse as main transcript	c.*83A>C		3_prime_UTR_variant	6/6	1	NM_003280.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0119

AC:

1808

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0392

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00681

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000426

Gnomad OTH

AF:

0.0105

GnomAD4 exome

AF:

0.00162

AC:

2281

AN:

1405104

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

1042

AN XY:

701812

show subpopulations

Gnomad4 AFR exome

AF:

0.0390

Gnomad4 AMR exome

AF:

0.00423

Gnomad4 ASJ exome

AF:

0.00560

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000355

Gnomad4 FIN exome

AF:

0.000437

Gnomad4 NFE exome

AF:

0.000365

Gnomad4 OTH exome

AF:

0.00440

GnomAD4 genome

AF:

0.0119

AC:

1814

AN:

152244

Hom.:

Cov.:

AF XY:

0.0111

AC XY:

824

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.0393

Gnomad4 AMR

AF:

0.00680

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.000426

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.00883

Hom.:

Bravo

AF:

0.0139

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 13

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Dilated cardiomyopathy 1Z

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

Cadd

Benign

Dann

Benign

0.73

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over