10-7709095-T-C

Variant names:

• chr10-7709095-T-C
• rs143197426
• NM_002216.3:c.266T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002216.3(ITIH2):​c.266T>C​(p.Met89Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M89R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITIH2 NM_002216.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.84
• Publications: 0 publications found

Genes affected

ITIH2 (HGNC:6167): (inter-alpha-trypsin inhibitor heavy chain 2) The inter-alpha-trypsin inhibitors (ITI) are a family of structurally related plasma serine protease inhibitors involved in extracellular matrix stabilization and in prevention of tumor metastasis. The ITI family contains multiple proteins made up of a light chain (see MIM 176870) and a variable number of heavy chains (Salier et al., 1987 [PubMed 2446322]; Himmelfarb et al., 2004 [PubMed 14744536]).[supplied by OMIM, Nov 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10002068).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002216.3. 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
	ITIH2	NM_002216.3	MANE Select	c.266T>C	p.Met89Thr	missense	Exon 4 of 21	NP_002207.2	P19823

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITIH2	ENST00000358415.9	TSL:1 MANE Select	c.266T>C	p.Met89Thr	missense	Exon 4 of 21	ENSP00000351190.4	P19823
	ITIH2	ENST00000899752.1		c.266T>C	p.Met89Thr	missense	Exon 4 of 22	ENSP00000569811.1
	ITIH2	ENST00000899753.1		c.266T>C	p.Met89Thr	missense	Exon 5 of 22	ENSP00000569812.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	14
DANN	Benign	0.53
DEOGEN2	Benign	0.0061	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.86	N
PhyloP100		2.8
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.097
Sift	Benign	0.052	T
Sift4G	Benign	0.17	T
Polyphen		0.0	B
Vest4		0.25
MutPred		0.54		Gain of glycosylation at M89 (P = 0.032)
MVP		0.081
MPC		0.098
ClinPred		0.048	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.24
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs143197426; hg19: chr10-7751058;