10-7705162-G-T

Variant names:

• chr10-7705162-G-T
• rs146658749
• NM_002216.3:c.139G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002216.3(ITIH2):​c.139G>T​(p.Ala47Ser) 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. A47T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ITIH2 NM_002216.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0330
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04221371).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITIH2	NM_002216.3	c.139G>T	p.Ala47Ser	missense_variant	Exon 2 of 21	ENST00000358415.9	NP_002207.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITIH2	ENST00000358415.9	c.139G>T	p.Ala47Ser	missense_variant	Exon 2 of 21	1	NM_002216.3	ENSP00000351190.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.84
DANN	Benign	0.29
DEOGEN2	Benign	0.019	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.53	T;T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.042	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N;.
PhyloP100		0.033
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.33	N;N
REVEL	Benign	0.063
Sift	Benign	0.77	T;T
Sift4G	Benign	0.76	T;T
Polyphen		0.0020	B;.
Vest4		0.088
MutPred		0.36		Gain of disorder (P = 0.0172);Gain of disorder (P = 0.0172);
MVP		0.16
MPC		0.077
ClinPred		0.038	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.033
gMVP		0.20
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs146658749; hg19: chr10-7747125; COSMIC: COSV64435535;