Genetic Variant TNNI3K:c.2352-14322G>A (chr1-74525912-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_015978.3(TNNI3K):c.2352-14322G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.473 in 152,026 control chromosomes in the GnomAD database, including 18,057 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.47 ( 18057 hom., cov: 32)

Consequence

TNNI3K
NM_015978.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.363

Publications

18 publications found

Variant links:

Genes affected

TNNI3K (HGNC:19661): (TNNI3 interacting kinase) This gene encodes a protein that belongs to the MAP kinase kinase kinase (MAPKKK) family of protein kinases. The protein contains ankyrin repeat, protein kinase and serine-rich domains and is thought to play a role in cardiac physiology. [provided by RefSeq, Sep 2012]

TNNI3K links:

FPGT-TNNI3K (HGNC:42952): (FPGT-TNNI3K readthrough) Enables protein C-terminus binding activity; protein kinase activity; and troponin I binding activity. Involved in protein phosphorylation and regulation of heart contraction. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

FPGT-TNNI3K links:

LRRC53 (HGNC:25255): (leucine rich repeat containing 53) Predicted to be integral component of membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

LRRC53 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.569 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015978.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNI3K	NM_015978.3	MANE Select	c.2352-14322G>A		intron	N/A	NP_057062.1
	FPGT-TNNI3K	NM_001112808.3		c.2655-14322G>A		intron	N/A	NP_001106279.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TNNI3K	ENST00000326637.8	TSL:1 MANE Select	c.2352-14322G>A	intron	N/A	ENSP00000322251.3
FPGT-TNNI3K	ENST00000557284.7	TSL:2	c.2655-14322G>A	intron	N/A	ENSP00000450895.3
FPGT-TNNI3K	ENST00000648585.1		n.*2258-14322G>A	intron	N/A	ENSP00000497631.1

Frequencies

GnomAD3 genomes

AF:

0.473

AC:

71894

AN:

151908

Hom.:

18052

Cov.:

show subpopulations

Gnomad AFR

AF:

0.317

Gnomad AMI

AF:

0.631

Gnomad AMR

AF:

0.451

Gnomad ASJ

AF:

0.617

Gnomad EAS

AF:

0.242

Gnomad SAS

AF:

0.466

Gnomad FIN

AF:

0.517

Gnomad MID

AF:

0.554

Gnomad NFE

AF:

0.573

Gnomad OTH

AF:

0.513

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.473

AC:

71910

AN:

152026

Hom.:

18057

Cov.:

AF XY:

0.467

AC XY:

34707

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.317

AC:

13143

AN:

41450

American (AMR)

AF:

0.451

AC:

6889

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.617

AC:

2140

AN:

3470

East Asian (EAS)

AF:

0.243

AC:

1259

AN:

5176

South Asian (SAS)

AF:

0.465

AC:

2236

AN:

4808

European-Finnish (FIN)

AF:

0.517

AC:

5455

AN:

10546

Middle Eastern (MID)

AF:

0.558

AC:

164

AN:

294

European-Non Finnish (NFE)

AF:

0.573

AC:

38966

AN:

67966

Other (OTH)

AF:

0.512

AC:

1084

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1852

3704

5556

7408

9260

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

658

1316

1974

2632

3290

<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:

0.536

Hom.:

30028

Bravo

AF:

0.458

Asia WGS

AF:

0.397

AC:

1383

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

7.2

(source)

DANN

Benign

0.73

PhyloP100

0.36

Mutation Taster

=100/0

polymorphism (auto)

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over