11-1840682-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003282.4(TNNI2):c.186+26G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 1,612,006 control chromosomes in the GnomAD database, including 34,991 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 2701 hom., cov: 34)

Exomes 𝑓: 0.20 ( 32290 hom. )

Consequence

TNNI2
NM_003282.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: 0.180

Publications

7 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 11-1840682-G-A is Benign according to our data. Variant chr11-1840682-G-A is described in ClinVar as Benign. ClinVar VariationId is 140483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TNNI2	NM_003282.4 link	c.186+26G>A	intron_variant	Intron 5 of 7	ENST00000381911.6	NP_003273.1	P48788-1
TNNI2	NM_001145829.2 link	c.186+26G>A	intron_variant	Intron 5 of 7		NP_001139301.1	P48788-1
TNNI2	NM_001145841.2 link	c.186+26G>A	intron_variant	Intron 3 of 5		NP_001139313.1	P48788-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNI2	ENST00000381911.6 link	c.186+26G>A		intron_variant	Intron 5 of 7	2	NM_003282.4	ENSP00000371336.1		P48788-1

Frequencies

GnomAD3 genomes

AF:

0.175

AC:

26637

AN:

151970

Hom.:

2700

Cov.:

show subpopulations

Gnomad AFR

AF:

0.101

Gnomad AMI

AF:

0.205

Gnomad AMR

AF:

0.162

Gnomad ASJ

AF:

0.345

Gnomad EAS

AF:

0.0535

Gnomad SAS

AF:

0.189

Gnomad FIN

AF:

0.171

Gnomad MID

AF:

0.279

Gnomad NFE

AF:

0.222

Gnomad OTH

AF:

0.207

GnomAD2 exomes

AF:

0.183

AC:

44897

AN:

245690

AF XY:

0.189

show subpopulations

Gnomad AFR exome

AF:

0.0931

Gnomad AMR exome

AF:

0.113

Gnomad ASJ exome

AF:

0.344

Gnomad EAS exome

AF:

0.0541

Gnomad FIN exome

AF:

0.168

Gnomad NFE exome

AF:

0.222

Gnomad OTH exome

AF:

0.217

GnomAD4 exome

AF:

0.204

AC:

298500

AN:

1459918

Hom.:

32290

Cov.:

AF XY:

0.206

AC XY:

149755

AN XY:

726252

show subpopulations

African (AFR)

AF:

0.0921

AC:

3084

AN:

33470

American (AMR)

AF:

0.118

AC:

5284

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.341

AC:

8902

AN:

26122

East Asian (EAS)

AF:

0.0643

AC:

2552

AN:

39660

South Asian (SAS)

AF:

0.195

AC:

16823

AN:

86226

European-Finnish (FIN)

AF:

0.168

AC:

8782

AN:

52126

Middle Eastern (MID)

AF:

0.283

AC:

1609

AN:

5694

European-Non Finnish (NFE)

AF:

0.215

AC:

239142

AN:

1111598

Other (OTH)

AF:

0.204

AC:

12322

AN:

60326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

14127

28254

42380

56507

70634

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8060

16120

24180

32240

40300

<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:

0.175

AC:

26646

AN:

152088

Hom.:

2701

Cov.:

AF XY:

0.172

AC XY:

12813

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.102

AC:

4215

AN:

41512

American (AMR)

AF:

0.161

AC:

2466

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.345

AC:

1199

AN:

3472

East Asian (EAS)

AF:

0.0540

AC:

278

AN:

5148

South Asian (SAS)

AF:

0.190

AC:

914

AN:

4808

European-Finnish (FIN)

AF:

0.171

AC:

1816

AN:

10598

Middle Eastern (MID)

AF:

0.262

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.222

AC:

15058

AN:

67944

Other (OTH)

AF:

0.207

AC:

437

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

1133

2266

3400

4533

5666

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

298

596

894

1192

1490

<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:

0.218

Hom.:

725

Bravo

AF:

0.169

Asia WGS

AF:

0.108

AC:

376

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

TNNI2 homepage - Leiden Muscular Dystrophy pages

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jun 26, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Distal arthrogryposis type 2B1

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: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

-0.83

CADD

Benign

6.0

(source)

DANN

Benign

0.84

PhyloP100

0.18

PromoterAI

0.030

Neutral

(source)

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over