chr1-201364342-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_ModeratePP5_Moderate

The NM_001276345.2(TNNT2):c.445C>A(p.Arg149Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R149H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TNNT2
NM_001276345.2 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.65

Publications

4 publications found

Variant links:

Genes affected

TNNT2 (HGNC:11949): (troponin T2, cardiac type) This gene encodes the cardiac isoform of troponin T. The encoded protein is the tropomyosin-binding subunit of the troponin complex, which is located on the thin filament of striated muscles and regulates muscle contraction in response to alterations in intracellular calcium ion concentration. Mutations in this gene have been associated with familial hypertrophic cardiomyopathy as well as with dilated cardiomyopathy. [provided by RefSeq, May 2022]

TNNT2 Gene-Disease associations (from GenCC):

dilated cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
dilated cardiomyopathy 1D
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
hypertrophic cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
hypertrophic cardiomyopathy 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
hypertrophic cardiomyopathy 3
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
cardiomyopathy, familial restrictive, 3
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial isolated restrictive cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
left ventricular noncompaction
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
cardiomyopathy
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

TNNT2 links:

ENSG00000286600 (HGNC:):

ENSG00000286600 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_001276345.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-201364341-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43642.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.884

PP5

Variant 1-201364342-G-T is Pathogenic according to our data. Variant chr1-201364342-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 430390.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNT2	NM_001276345.2 link	c.445C>A	p.Arg149Ser	missense_variant	Exon 11 of 17	ENST00000656932.1	NP_001263274.1	P45379-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1 link	c.445C>A	p.Arg149Ser	missense_variant	Exon 11 of 17		NM_001276345.2	ENSP00000499593.1		P45379-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1460878

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726774

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52536

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111964

Other (OTH)

AF:

0.00

AC:

AN:

60380

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Sep 17, 2015

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The R139S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R139S variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R139S variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in this same residue (R139C, R139H) and in nearby residues (R134G, Q138H, R141W, R141Q) have been reported in the Human Gene Mutation Database in association with DCM (Stenson et al., 2014), supporting the functional importance of this region of the protein.Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

CardioboostCm

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

.;.;.;.;D;.;.;.;.;.;D;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Benign

0.71

LIST_S2

Pathogenic

0.99

.;D;D;D;D;D;D;.;.;D;.;.

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.88

D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.94

MutationAssessor

Pathogenic

3.1

.;.;.;.;M;.;.;.;.;.;.;.

PhyloP100

2.6

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-5.2

D;D;D;.;D;N;D;.;D;D;D;D

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

D;D;D;.;D;D;D;.;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D;D;D;D;D;.;D

Polyphen

1.0, 0.99

.;.;.;.;D;.;.;.;.;.;D;.

Vest4

0.77

MutPred

0.50

.;.;.;.;Gain of phosphorylation at R149 (P = 0.0019);.;.;.;.;.;.;Gain of phosphorylation at R149 (P = 0.0019);

MVP

0.99

MPC

1.3

ClinPred

1.0

GERP RS

4.3

Varity_R

0.92

gMVP

0.99

Mutation Taster

=30/70

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over