Genetic Variant TNNT2:p.Arg288Cys (chr1-201359245-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 4P and 3B. PM1PM5BP4_ModerateBS1_Supporting

The NM_001276345.2(TNNT2):c.862C>T(p.Arg288Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000513 in 1,611,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R288P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00042 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00052 ( 0 hom. )

Consequence

TNNT2
NM_001276345.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9U:23

Conservation

PhyloP100: 0.770

Publications

78 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: Uncertain_significance. The variant received 1 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 21 uncertain in NM_001276345.2

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-201359244-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 177635.

BP4

Computational evidence support a benign effect (MetaRNN=0.1970368).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000421 (64/152172) while in subpopulation NFE AF = 0.000661 (45/68030). AF 95% confidence interval is 0.000508. There are 0 homozygotes in GnomAd4. There are 32 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001276345.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TNNT2	NM_001276345.2	MANE Select	c.862C>T	p.Arg288Cys	missense	Exon 17 of 17	NP_001263274.1
TNNT2	NM_000364.4		c.853C>T	p.Arg285Cys	missense	Exon 16 of 16	NP_000355.2
TNNT2	NM_001406723.1		c.853C>T	p.Arg285Cys	missense	Exon 16 of 16	NP_001393652.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TNNT2	ENST00000656932.1	MANE Select	c.862C>T	p.Arg288Cys	missense	Exon 17 of 17	ENSP00000499593.1
TNNT2	ENST00000367322.6	TSL:1	c.820C>T	p.Arg274Cys	missense	Exon 15 of 15	ENSP00000356291.2
TNNT2	ENST00000367320.6	TSL:1	c.733C>T	p.Arg245Cys	missense	Exon 15 of 15	ENSP00000356289.2

Frequencies

GnomAD3 genomes

AF:

0.000421

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000661

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.000360

AC:

AN:

244204

AF XY:

0.000425

show subpopulations

Gnomad AFR exome

AF:

0.000255

Gnomad AMR exome

AF:

0.000265

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000143

Gnomad NFE exome

AF:

0.000626

Gnomad OTH exome

AF:

0.000504

GnomAD4 exome

AF:

0.000523

AC:

763

AN:

1459038

Hom.:

Cov.:

AF XY:

0.000505

AC XY:

366

AN XY:

725306

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33460

American (AMR)

AF:

0.000338

AC:

AN:

44398

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26034

East Asian (EAS)

AF:

0.00

AC:

AN:

39650

South Asian (SAS)

AF:

0.0000118

AC:

AN:

85042

European-Finnish (FIN)

AF:

0.0000751

AC:

AN:

53238

Middle Eastern (MID)

AF:

0.000525

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.000642

AC:

713

AN:

1111204

Other (OTH)

AF:

0.000381

AC:

AN:

60294

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

137

183

229

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

112

140

<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:

0.000421

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.000431

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41444

American (AMR)

AF:

0.000393

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000661

AC:

AN:

68030

Other (OTH)

AF:

0.000958

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000556

Hom.:

Bravo

AF:

0.000416

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.000354

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (9)

Dilated cardiomyopathy 1D;C1861864:Hypertrophic cardiomyopathy 2;C2676271:Cardiomyopathy, familial restrictive, 3 (5)

Hypertrophic cardiomyopathy 2 (5)

Dilated cardiomyopathy 1D (3)

Cardiomyopathy (2)

Cardiovascular phenotype (2)

Hypertrophic cardiomyopathy (2)

not specified (2)

Costello syndrome (1)

Hypertrophic cardiomyopathy 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

CardioboostCm

Uncertain

0.14

BayesDel_addAF

Benign

-0.073

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Benign

0.34

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.43

MetaRNN

Benign

0.20

MetaSVM

Uncertain

0.11

MutationAssessor

Uncertain

2.0

PhyloP100

0.77

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.63

Sift

Benign

0.062

Sift4G

Uncertain

0.025

Polyphen

1.0

Vest4

0.52

MVP

0.92

MPC

1.7

ClinPred

0.13

GERP RS

3.0

Varity_R

0.30

gMVP

0.50

Mutation Taster

=0/100

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over