chr11-1839074-G-A

Variant names:

• chr11-1839074-G-A
• rs61867133
• NM_003282.4:c.-23+41G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003282.4(TNNI2):​c.-23+41G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 152,790 control chromosomes in the GnomAD database, including 2,005 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1993 hom., cov: 32)
  • Exomes 𝑓: 0.15 (12 hom.)
• Consequence: TNNI2 NM_003282.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.86
• Publications: 1 publications found

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: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• digitotalar dysmorphism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Sheldon-hall syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 11-1839074-G-A is Benign according to our data. Variant chr11-1839074-G-A is described in ClinVar as Benign. ClinVar VariationId is 1231135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNI2	NM_003282.4	MANE Select	c.-23+41G>A		intron	N/A	NP_003273.1	P48788-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNI2	ENST00000381911.6	TSL:2 MANE Select	c.-23+41G>A		intron	N/A	ENSP00000371336.1	P48788-1

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21828 AN: 152006 Hom.: 1990 Cov.: 32

Gnomad AFR AF: 0.0436

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.0385

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.202

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.153

GnomAD4 exome AF: 0.153 AC: 102 AN: 666 Hom.: 12 Cov.: 0 AF XY: 0.150 AC XY: 61 AN XY: 408

African (AFR) AF: 0.00 AC: 0 AN: 6

American (AMR) AF: 0.182 AC: 12 AN: 66

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AF: 0.00 AC: 0 AN: 16

South Asian (SAS) AF: 0.131 AC: 16 AN: 122

European-Finnish (FIN) AF: 0.500 AC: 3 AN: 6

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.163 AC: 69 AN: 424

Other (OTH) AF: 0.100 AC: 2 AN: 20

GnomAD4 genome AF: 0.143 AC: 21825 AN: 152124 Hom.: 1993 Cov.: 32 AF XY: 0.145 AC XY: 10744 AN XY: 74350

African (AFR) AF: 0.0435 AC: 1807 AN: 41568

American (AMR) AF: 0.199 AC: 3044 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 482 AN: 3470

East Asian (EAS) AF: 0.0386 AC: 199 AN: 5154

South Asian (SAS) AF: 0.163 AC: 785 AN: 4822

European-Finnish (FIN) AF: 0.202 AC: 2129 AN: 10558

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.189 AC: 12866 AN: 67942

Other (OTH) AF: 0.152 AC: 321 AN: 2114

Alfa AF: 0.183 Hom.: 1204

Bravo AF: 0.139

Asia WGS AF: 0.116 AC: 403 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.0020
DANN	Benign	0.76
PhyloP100		-1.9
PromoterAI		-0.058	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61867133; hg19: chr11-1860304;