11-1840530-T-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_003282.4(TNNI2):​c.60T>A​(p.Ser20Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S20S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 36)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TNNI2 NM_003282.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 6 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.61809 (below the threshold of 3.09). Trascript score misZ: 1.172 (below the threshold of 3.09). GenCC associations: The gene is linked to distal arthrogryposis type 2B1, digitotalar dysmorphism, Sheldon-hall syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNI2	NM_003282.4	c.60T>A	p.Ser20Arg	missense_variant, splice_region_variant	Exon 5 of 8	ENST00000381911.6	NP_003273.1
TNNI2	NM_001145829.2	c.60T>A	p.Ser20Arg	missense_variant, splice_region_variant	Exon 5 of 8		NP_001139301.1
TNNI2	NM_001145841.2	c.60T>A	p.Ser20Arg	missense_variant, splice_region_variant	Exon 3 of 6		NP_001139313.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNI2	ENST00000381911.6	c.60T>A	p.Ser20Arg	missense_variant, splice_region_variant	Exon 5 of 8	2	NM_003282.4	ENSP00000371336.1

Frequencies

GnomAD3 genomes Cov.: 36

GnomAD2 exomes AF: 0.00000409 AC: 1 AN: 244286 AF XY: 0.00000749

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459640 Hom.: 0 Cov.: 106 AF XY: 0.00000138 AC XY: 1 AN XY: 726100

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39674

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51918

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111542

Other (OTH) AF: 0.00 AC: 0 AN: 60308

GnomAD4 genome Cov.: 36

ExAC AF: 0.00000830 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D;D;.;D;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.42	N
LIST_S2	Uncertain	0.95	.;.;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	3.0	M;M;.;M;M
PhyloP100		-0.30
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.5	D;D;.;D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0030	D;D;.;D;D
Sift4G	Benign	0.12	T;T;T;T;T
Polyphen		1.0	D;D;.;D;.
Vest4		0.66
MutPred		0.68		Gain of MoRF binding (P = 0.0342);Gain of MoRF binding (P = 0.0342);Gain of MoRF binding (P = 0.0342);Gain of MoRF binding (P = 0.0342);Gain of MoRF binding (P = 0.0342);
MVP		0.94
MPC		0.93
ClinPred		0.92	D
GERP RS		-1.4
PromoterAI		0.016	Neutral
Varity_R		0.75
gMVP		0.41
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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;