dbSNP rs3730244: TNNT2:c.*71C>T (chr1-201359139-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001276345.2(TNNT2):c.*71C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0225 in 1,568,226 control chromosomes in the GnomAD database, including 475 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 30 hom., cov: 32)

Exomes 𝑓: 0.023 ( 445 hom. )

Consequence

TNNT2
NM_001276345.2 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -2.51

Publications

5 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 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
hypertrophic cardiomyopathy 3
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
cardiomyopathy, familial restrictive, 3
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
hypertrophic cardiomyopathy
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 1-201359139-G-A is Benign according to our data. Variant chr1-201359139-G-A is described in ClinVar as Benign. ClinVar VariationId is 1239408.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.017 (2590/152300) while in subpopulation NFE AF = 0.0276 (1874/68018). AF 95% confidence interval is 0.0265. There are 30 homozygotes in GnomAd4. There are 1209 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 30 AD,AR gene

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	Effect	Exon Rank	Protein	UniProt
TNNT2	NM_001276345.2	MANE Select	c.*71C>T	3_prime_UTR	Exon 17 of 17	NP_001263274.1	P45379-1
TNNT2	NM_000364.4		c.*71C>T	3_prime_UTR	Exon 16 of 16	NP_000355.2
TNNT2	NM_001406723.1		c.*71C>T	3_prime_UTR	Exon 16 of 16	NP_001393652.1	P45379-10

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TNNT2	ENST00000656932.1	MANE Select	c.*71C>T	3_prime_UTR	Exon 17 of 17	ENSP00000499593.1	P45379-1
TNNT2	ENST00000367322.6	TSL:1	c.*71C>T	3_prime_UTR	Exon 15 of 15	ENSP00000356291.2	A0A499FJM7
TNNT2	ENST00000367320.6	TSL:1	c.*71C>T	3_prime_UTR	Exon 15 of 15	ENSP00000356289.2	P45379-12

Frequencies

GnomAD3 genomes

AF:

0.0170

AC:

2590

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00454

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0171

Gnomad ASJ

AF:

0.00922

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0178

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0275

Gnomad OTH

AF:

0.0163

GnomAD4 exome

AF:

0.0230

AC:

32632

AN:

1415926

Hom.:

445

Cov.:

AF XY:

0.0224

AC XY:

15712

AN XY:

700412

show subpopulations

African (AFR)

AF:

0.00363

AC:

120

AN:

33062

American (AMR)

AF:

0.00988

AC:

366

AN:

37036

Ashkenazi Jewish (ASJ)

AF:

0.0117

AC:

296

AN:

25282

East Asian (EAS)

AF:

0.0000260

AC:

AN:

38398

South Asian (SAS)

AF:

0.00113

AC:

AN:

80786

European-Finnish (FIN)

AF:

0.0198

AC:

999

AN:

50538

Middle Eastern (MID)

AF:

0.00851

AC:

AN:

4464

European-Non Finnish (NFE)

AF:

0.0273

AC:

29643

AN:

1087688

Other (OTH)

AF:

0.0184

AC:

1078

AN:

58672

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1767

3533

5300

7066

8833

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1114

2228

3342

4456

5570

<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:

0.0170

AC:

2590

AN:

152300

Hom.:

Cov.:

AF XY:

0.0162

AC XY:

1209

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00452

AC:

188

AN:

41558

American (AMR)

AF:

0.0171

AC:

262

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00922

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00166

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0178

AC:

189

AN:

10626

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0276

AC:

1874

AN:

68018

Other (OTH)

AF:

0.0161

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

140

279

419

558

698

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.0199

Hom.:

Bravo

AF:

0.0156

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.039

(source)

DANN

Benign

0.39

PhyloP100

-2.5

Mutation Taster

=100/0

polymorphism

(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