11-1840530-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003282.4(TNNI2):c.60T>C(p.Ser20Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.871 in 1,611,762 control chromosomes in the GnomAD database, including 613,286 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.83 ( 52802 hom., cov: 36)

Exomes 𝑓: 0.88 ( 560484 hom. )

Consequence

TNNI2
NM_003282.4 splice_region, synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: -0.300

Publications

21 publications found

Variant links:

Genes affected

TNNI2 (HGNC:11946): (troponin I2, fast skeletal type) This gene encodes a fast-twitch skeletal muscle protein, a member of the troponin I gene family, and a component of the troponin complex including troponin T, troponin C and troponin I subunits. The troponin complex, along with tropomyosin, is responsible for the calcium-dependent regulation of striated muscle contraction. Mouse studies show that this component is also present in vascular smooth muscle and may play a role in regulation of smooth muscle function. In addition to muscle tissues, this protein is found in corneal epithelium, cartilage where it is an inhibitor of angiogenesis to inhibit tumor growth and metastasis, and mammary gland where it functions as a co-activator of estrogen receptor-related receptor alpha. This protein also suppresses tumor growth in human ovarian carcinoma. Mutations in this gene cause myopathy and distal arthrogryposis type 2B. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2009]

TNNI2 Gene-Disease associations (from GenCC):

distal arthrogryposis type 2B1
Inheritance: AD, AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
digitotalar dysmorphism
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Sheldon-hall syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TNNI2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 11-1840530-T-C is Benign according to our data. Variant chr11-1840530-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.3 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.963 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TNNI2	NM_003282.4 link	c.60T>C	p.Ser20Ser	splice_region_variant, synonymous_variant	Exon 5 of 8	ENST00000381911.6	NP_003273.1
TNNI2	NM_001145829.2 link	c.60T>C	p.Ser20Ser	splice_region_variant, synonymous_variant	Exon 5 of 8		NP_001139301.1
TNNI2	NM_001145841.2 link	c.60T>C	p.Ser20Ser	splice_region_variant, synonymous_variant	Exon 3 of 6		NP_001139313.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNI2	ENST00000381911.6 link	c.60T>C	p.Ser20Ser	splice_region_variant, synonymous_variant	Exon 5 of 8	2	NM_003282.4	ENSP00000371336.1

Frequencies

GnomAD3 genomes

AF:

0.827

AC:

125656

AN:

152026

Hom.:

52761

Cov.:

show subpopulations

Gnomad AFR

AF:

0.666

Gnomad AMI

AF:

0.836

Gnomad AMR

AF:

0.875

Gnomad ASJ

AF:

0.864

Gnomad EAS

AF:

0.985

Gnomad SAS

AF:

0.878

Gnomad FIN

AF:

0.938

Gnomad MID

AF:

0.841

Gnomad NFE

AF:

0.877

Gnomad OTH

AF:

0.844

GnomAD2 exomes

AF:

0.879

AC:

214784

AN:

244286

AF XY:

0.880

show subpopulations

Gnomad AFR exome

AF:

0.652

Gnomad AMR exome

AF:

0.900

Gnomad ASJ exome

AF:

0.860

Gnomad EAS exome

AF:

0.988

Gnomad FIN exome

AF:

0.932

Gnomad NFE exome

AF:

0.878

Gnomad OTH exome

AF:

0.879

GnomAD4 exome

AF:

0.875

AC:

1277376

AN:

1459618

Hom.:

560484

Cov.:

106

AF XY:

0.876

AC XY:

636062

AN XY:

726092

show subpopulations

African (AFR)

AF:

0.652

AC:

21832

AN:

33466

American (AMR)

AF:

0.898

AC:

40105

AN:

44646

Ashkenazi Jewish (ASJ)

AF:

0.856

AC:

22361

AN:

26108

East Asian (EAS)

AF:

0.992

AC:

39347

AN:

39674

South Asian (SAS)

AF:

0.877

AC:

75587

AN:

86222

European-Finnish (FIN)

AF:

0.936

AC:

48565

AN:

51912

Middle Eastern (MID)

AF:

0.841

AC:

4837

AN:

5752

European-Non Finnish (NFE)

AF:

0.875

AC:

972385

AN:

1111536

Other (OTH)

AF:

0.868

AC:

52357

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

11223

22446

33668

44891

56114

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21290

42580

63870

85160

106450

<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:

0.827

AC:

125752

AN:

152144

Hom.:

52802

Cov.:

AF XY:

0.832

AC XY:

61914

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.666

AC:

27598

AN:

41422

American (AMR)

AF:

0.876

AC:

13405

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.864

AC:

3000

AN:

3472

East Asian (EAS)

AF:

0.985

AC:

5095

AN:

5172

South Asian (SAS)

AF:

0.879

AC:

4244

AN:

4830

European-Finnish (FIN)

AF:

0.938

AC:

9972

AN:

10626

Middle Eastern (MID)

AF:

0.836

AC:

244

AN:

292

European-Non Finnish (NFE)

AF:

0.877

AC:

59643

AN:

67996

Other (OTH)

AF:

0.846

AC:

1789

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.524

Heterozygous variant carriers

1121

2243

3364

4486

5607

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

882

1764

2646

3528

4410

<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:

0.862

Hom.:

113031

Bravo

AF:

0.815

Asia WGS

AF:

0.928

AC:

3226

AN:

3478

EpiCase

AF:

0.876

EpiControl

AF:

0.869

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 25, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 05, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Distal arthrogryposis type 2B1

Benign:3

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:1Other:1

TNNI2 homepage - Leiden Muscular Dystrophy pages

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Arthrogryposis multiplex congenita

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

6.9

(source)

DANN

Benign

0.55

PhyloP100

-0.30

PromoterAI

-0.0014

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over