Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_003282.4(TNNI2):c.54G>C(p.Leu18Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0004 in 1,610,904 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00037 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00040 ( 1 hom. )

Consequence

TNNI2
NM_003282.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 2.54

Publications

0 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 11-1840441-G-C is Benign according to our data. Variant chr11-1840441-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 287318.

BP7

Synonymous conserved (PhyloP=2.54 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003282.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TNNI2	NM_003282.4	MANE Select	c.54G>C	p.Leu18Leu	synonymous	Exon 4 of 8	NP_003273.1
TNNI2	NM_001145829.2		c.54G>C	p.Leu18Leu	synonymous	Exon 4 of 8	NP_001139301.1
TNNI2	NM_001145841.2		c.54G>C	p.Leu18Leu	synonymous	Exon 2 of 6	NP_001139313.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TNNI2	ENST00000381911.6	TSL:2 MANE Select	c.54G>C	p.Leu18Leu	synonymous	Exon 4 of 8	ENSP00000371336.1
TNNI2	ENST00000252898.11	TSL:3	c.54G>C	p.Leu18Leu	synonymous	Exon 3 of 7	ENSP00000252898.7
TNNI2	ENST00000381905.3	TSL:3	c.54G>C	p.Leu18Leu	synonymous	Exon 2 of 6	ENSP00000371330.3

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000580

AC:

138

AN:

238012

AF XY:

0.000619

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000294

Gnomad ASJ exome

AF:

0.00847

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000282

Gnomad OTH exome

AF:

0.00120

GnomAD4 exome

AF:

0.000404

AC:

589

AN:

1458524

Hom.:

Cov.:

AF XY:

0.000398

AC XY:

289

AN XY:

725550

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33468

American (AMR)

AF:

0.000426

AC:

AN:

44612

Ashkenazi Jewish (ASJ)

AF:

0.00798

AC:

208

AN:

26066

East Asian (EAS)

AF:

0.00

AC:

AN:

39660

South Asian (SAS)

AF:

0.000267

AC:

AN:

86128

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51046

Middle Eastern (MID)

AF:

0.00332

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.000227

AC:

252

AN:

1111572

Other (OTH)

AF:

0.00110

AC:

AN:

60250

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

124

166

207

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000368

AC:

AN:

152380

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41592

American (AMR)

AF:

0.0000653

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00893

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

68034

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00139

Hom.:

Bravo

AF:

0.000408

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.000596

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Arthrogryposis multiplex congenita (1)

Arthrogryposis multiplex congenita distal (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

8.8

(source)

DANN

Benign

0.92

PhyloP100

2.5

PromoterAI

0.040

Neutral

(source)

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

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

rs181679318

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over