11-1840531-G-A

Position:

chr11-1840531-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4BS2

The NM_003282.4(TNNI2):c.61G>A(p.Val21Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 1,612,068 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00019 ( 1 hom. )

Consequence

TNNI2
NM_003282.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 2.13

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1

In a chain Troponin I, fast skeletal muscle (size 180) in uniprot entity TNNI2_HUMAN there are 17 pathogenic changes around while only 1 benign (94%) in NM_003282.4

BP4

Computational evidence support a benign effect (MetaRNN=0.3103873).

BS2

High AC in GnomAd4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TNNI2	NM_003282.4 linkuse as main transcript	c.61G>A	p.Val21Met	missense_variant	5/8	ENST00000381911.6
TNNI2	NM_001145829.2 linkuse as main transcript	c.61G>A	p.Val21Met	missense_variant	5/8
TNNI2	NM_001145841.2 linkuse as main transcript	c.61G>A	p.Val21Met	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNI2	ENST00000381911.6 linkuse as main transcript	c.61G>A	p.Val21Met	missense_variant	5/8	2	NM_003282.4	A1	P48788-1

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000225

AC:

AN:

244928

Hom.:

AF XY:

0.000247

AC XY:

AN XY:

133864

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000506

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.0000475

Gnomad NFE exome

AF:

0.000419

Gnomad OTH exome

AF:

0.000335

GnomAD4 exome

AF:

0.000193

AC:

282

AN:

1459848

Hom.:

Cov.:

AF XY:

0.000219

AC XY:

159

AN XY:

726234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.000421

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000154

Gnomad4 NFE exome

AF:

0.000229

Gnomad4 OTH exome

AF:

0.0000995

GnomAD4 genome

AF:

0.000171

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000382

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000475

Hom.:

Bravo

AF:

0.000185

ExAC

AF:

0.000232

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 07, 2022	See Variant Classification Assertion Criteria. -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The TNNI2 p.Val21Met variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs200110633) and in ClinVar (classified as a VUS by Illumina for Arthrogryposis Multiplex Congenita and Distal Arthrogryposis Multiplex Congenita, and as likely benign by GeneDx). The variant was also identified in control databases in 62 of 276310 chromosomes at a frequency of 0.000224 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 5 of 10172 chromosomes (freq: 0.000492), European (non-Finnish) in 53 of 125294 chromosomes (freq: 0.000423), Other in 2 of 7066 chromosomes (freq: 0.000283), European (Finnish) in 1 of 24506 chromosomes (freq: 0.000041) and South Asian in 1 of 30528 chromosomes (freq: 0.000033); it was not observed in the African, Latino or East Asian populations. The p.Val21 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and only two of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2017	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2021

The c.61G>A (p.V21M) alteration is located in exon 5 (coding exon 4) of the TNNI2 gene. This alteration results from a G to A substitution at nucleotide position 61, causing the valine (V) at amino acid position 21 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Arthrogryposis multiplex congenita

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Arthrogryposis multiplex congenita distal

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.49

T;T;.;T;.

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.76

M_CAP

Pathogenic

0.61

MetaRNN

Benign

0.31

T;T;T;T;T

MetaSVM

Uncertain

0.20

MutationAssessor

Benign

0.46

N;N;.;N;N

MutationTaster

Benign

0.53

N;N;N;N

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

0.17

N;N;.;N;N

REVEL

Uncertain

0.32

Sift

Benign

0.042

D;D;.;D;D

Sift4G

Uncertain

0.032

D;D;D;D;D

Polyphen

0.025

B;B;.;B;.

Vest4

0.27

MVP

0.90

MPC

0.25

ClinPred

0.040

GERP RS

2.8

Varity_R

0.076

gMVP

0.14

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over