rs2271441

Variant names:

• chr11-1840682-G-A
• rs2271441
• NM_003282.4:c.186+26G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-1840682-G-A
• chr11-1840682-G-C
• chr11-1840682-G-T

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.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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 0.180
• Publications: 7 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=-0.83).
• 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.

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.186+26G>A		intron	N/A	NP_003273.1	P48788-1
	TNNI2	NM_001145829.2		c.186+26G>A		intron	N/A	NP_001139301.1	P48788-1
	TNNI2	NM_001145841.2		c.186+26G>A		intron	N/A	NP_001139313.1	P48788-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNI2	ENST00000381911.6	TSL:2 MANE Select	c.186+26G>A		intron	N/A	ENSP00000371336.1	P48788-1
	TNNI2	ENST00000252898.11	TSL:3	c.186+26G>A		intron	N/A	ENSP00000252898.7	P48788-1
	TNNI2	ENST00000381905.3	TSL:3	c.186+26G>A		intron	N/A	ENSP00000371330.3	P48788-2

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26637 AN: 151970 Hom.: 2700 Cov.: 34

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

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.: 44 AF XY: 0.206 AC XY: 149755 AN XY: 726252

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

GnomAD4 genome AF: 0.175 AC: 26646 AN: 152088 Hom.: 2701 Cov.: 34 AF XY: 0.172 AC XY: 12813 AN XY: 74348

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: 76 AN: 290

European-Non Finnish (NFE) AF: 0.222 AC: 15058 AN: 67944

Other (OTH) AF: 0.207 AC: 437 AN: 2114

Alfa AF: 0.218 Hom.: 725

Bravo AF: 0.169

Asia WGS AF: 0.108 AC: 376 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)
-	-	1	Distal arthrogryposis type 2B1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.0
DANN	Benign	0.84
PhyloP100		0.18
PromoterAI		0.030	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: rs2271441; hg19: chr11-1861912; COSMIC: COSV53290331; COSMIC: COSV53290331;