Genetic Variant TNNI1:p.Thr51Lys (chr1-201414555-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_003281.4(TNNI1):c.152C>A(p.Thr51Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T51M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TNNI1
NM_003281.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.57

Publications

0 publications found

Variant links:

Genes affected

TNNI1 (HGNC:11945): (troponin I1, slow skeletal type) Troponin proteins associate with tropomyosin and regulate the calcium sensitivity of the myofibril contractile apparatus of striated muscles. Troponin I (TnI), along with troponin T (TnT) and troponin C (TnC), is one of 3 subunits that form the troponin complex of the thin filaments of striated muscle. TnI is the inhibitory subunit; blocking actin-myosin interactions and thereby mediating striated muscle relaxation. The TnI subfamily contains three genes: TnI-skeletal-fast-twitch, TnI-skeletal-slow-twitch, and TnI-cardiac. The TnI-fast and TnI-slow genes are expressed in fast-twitch and slow-twitch skeletal muscle fibers, respectively, while the TnI-cardiac gene is expressed exclusively in cardiac muscle tissue. This gene encodes the Troponin-I-skeletal-slow-twitch protein. This gene is expressed in cardiac and skeletal muscle during early development but is restricted to slow-twitch skeletal muscle fibers in adults. The encoded protein prevents muscle contraction by inhibiting calcium-mediated conformational changes in actin-myosin complexes. [provided by RefSeq, Jul 2008]

TNNI1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.37179178).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNI1	NM_003281.4 link	c.152C>A	p.Thr51Lys	missense_variant	Exon 5 of 9	ENST00000361379.9	NP_003272.3	P19237

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNI1	ENST00000361379.9 link	c.152C>A	p.Thr51Lys	missense_variant	Exon 5 of 9	5	NM_003281.4	ENSP00000354488.4		P19237

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000402

AC:

AN:

248916

AF XY:

0.00000742

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000889

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460436

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726484

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44642

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26076

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86036

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52828

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111660

Other (OTH)

AF:

0.0000166

AC:

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.065

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

T;T;T;.;T;T;.

Eigen

Benign

-0.039

Eigen_PC

Benign

0.14

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.91

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

M_CAP

Benign

0.071

MetaRNN

Benign

0.37

T;T;T;T;T;T;T

MetaSVM

Uncertain

0.16

MutationAssessor

Benign

-0.30

.;N;N;.;N;.;.

PhyloP100

4.6

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.50

.;N;N;N;N;N;N

REVEL

Uncertain

0.34

Sift

Uncertain

0.022

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

Sift4G

Uncertain

0.050

T;D;D;D;D;T;T

Polyphen

0.011

.;B;B;.;B;.;.

Vest4

0.34

MutPred

0.56

Gain of methylation at T51 (P = 0.0114);Gain of methylation at T51 (P = 0.0114);Gain of methylation at T51 (P = 0.0114);Gain of methylation at T51 (P = 0.0114);Gain of methylation at T51 (P = 0.0114);.;Gain of methylation at T51 (P = 0.0114);

MVP

0.96

MPC

0.89

ClinPred

0.72

GERP RS

4.8

Varity_R

0.17

gMVP

0.46

Mutation Taster

=66/34

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over