11-1840530-T-C

Variant names:

• chr11-1840530-T-C
• rs907610
• NM_003282.4:c.60T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003282.4(TNNI2):​c.60T>C​(p.Ser20Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.871 in 1,611,762 control chromosomes in the GnomAD database, including 613,286 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (52802 hom., cov: 36)
  • Exomes 𝑓: 0.88 (560484 hom.)
• Consequence: TNNI2 NM_003282.4 splice_region, synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -0.300
• Publications: 21 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: 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 11-1840530-T-C is Benign according to our data. Variant chr11-1840530-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.3 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.963 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.60T>C	p.Ser20Ser	splice_region synonymous	Exon 5 of 8	NP_003273.1	P48788-1
	TNNI2	NM_001145829.2		c.60T>C	p.Ser20Ser	splice_region synonymous	Exon 5 of 8	NP_001139301.1	P48788-1
	TNNI2	NM_001145841.2		c.60T>C	p.Ser20Ser	splice_region synonymous	Exon 3 of 6	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.60T>C	p.Ser20Ser	splice_region synonymous	Exon 5 of 8	ENSP00000371336.1	P48788-1
	TNNI2	ENST00000252898.11	TSL:3	c.60T>C	p.Ser20Ser	splice_region synonymous	Exon 4 of 7	ENSP00000252898.7	P48788-1
	TNNI2	ENST00000381905.3	TSL:3	c.60T>C	p.Ser20Ser	splice_region synonymous	Exon 3 of 6	ENSP00000371330.3	P48788-2

Frequencies

GnomAD3 genomes AF: 0.827 AC: 125656 AN: 152026 Hom.: 52761 Cov.: 36

Gnomad AFR AF: 0.666

Gnomad AMI AF: 0.836

Gnomad AMR AF: 0.875

Gnomad ASJ AF: 0.864

Gnomad EAS AF: 0.985

Gnomad SAS AF: 0.878

Gnomad FIN AF: 0.938

Gnomad MID AF: 0.841

Gnomad NFE AF: 0.877

Gnomad OTH AF: 0.844

GnomAD2 exomes AF: 0.879 AC: 214784 AN: 244286 AF XY: 0.880

Gnomad AFR exome AF: 0.652

Gnomad AMR exome AF: 0.900

Gnomad ASJ exome AF: 0.860

Gnomad EAS exome AF: 0.988

Gnomad FIN exome AF: 0.932

Gnomad NFE exome AF: 0.878

Gnomad OTH exome AF: 0.879

GnomAD4 exome AF: 0.875 AC: 1277376 AN: 1459618 Hom.: 560484 Cov.: 106 AF XY: 0.876 AC XY: 636062 AN XY: 726092

African (AFR) AF: 0.652 AC: 21832 AN: 33466

American (AMR) AF: 0.898 AC: 40105 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.856 AC: 22361 AN: 26108

East Asian (EAS) AF: 0.992 AC: 39347 AN: 39674

South Asian (SAS) AF: 0.877 AC: 75587 AN: 86222

European-Finnish (FIN) AF: 0.936 AC: 48565 AN: 51912

Middle Eastern (MID) AF: 0.841 AC: 4837 AN: 5752

European-Non Finnish (NFE) AF: 0.875 AC: 972385 AN: 1111536

Other (OTH) AF: 0.868 AC: 52357 AN: 60302

GnomAD4 genome AF: 0.827 AC: 125752 AN: 152144 Hom.: 52802 Cov.: 36 AF XY: 0.832 AC XY: 61914 AN XY: 74380

African (AFR) AF: 0.666 AC: 27598 AN: 41422

American (AMR) AF: 0.876 AC: 13405 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.864 AC: 3000 AN: 3472

East Asian (EAS) AF: 0.985 AC: 5095 AN: 5172

South Asian (SAS) AF: 0.879 AC: 4244 AN: 4830

European-Finnish (FIN) AF: 0.938 AC: 9972 AN: 10626

Middle Eastern (MID) AF: 0.836 AC: 244 AN: 292

European-Non Finnish (NFE) AF: 0.877 AC: 59643 AN: 67996

Other (OTH) AF: 0.846 AC: 1789 AN: 2114

Alfa AF: 0.862 Hom.: 113031

Bravo AF: 0.815

Asia WGS AF: 0.928 AC: 3226 AN: 3478

EpiCase AF: 0.876

EpiControl AF: 0.869

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Distal arthrogryposis type 2B1 (3)
-	-	1	Arthrogryposis multiplex congenita (1)
-	-	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	6.9
DANN	Benign	0.55
PhyloP100		-0.30
PromoterAI		-0.0014	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs907610; hg19: chr11-1861760; COSMIC: COSV53290568; COSMIC: COSV53290568;