rs7084817

Positions:

• chr10-7732395-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002216.3(ITIH2):​c.1705C>G​(p.Leu569Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0469 in 1,613,892 control chromosomes in the GnomAD database, including 2,016 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.035 (121 hom., cov: 32)
  • Exomes 𝑓: 0.048 (1895 hom.)
• Consequence: ITIH2 NM_002216.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.26

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033824742).
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0739 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITIH2	NM_002216.3	c.1705C>G	p.Leu569Val	missense_variant	14/21	ENST00000358415.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITIH2	ENST00000358415.9	c.1705C>G	p.Leu569Val	missense_variant	14/21	1	NM_002216.3	P1
ITIH2	ENST00000379587.4	c.1672C>G	p.Leu558Val	missense_variant	13/20	5
ITIH2	ENST00000477751.1	n.513C>G		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.0355 AC: 5398 AN: 152148 Hom.: 121 Cov.: 32

Gnomad AFR AF: 0.0130

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0245

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.00674

Gnomad SAS AF: 0.0419

Gnomad FIN AF: 0.0591

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0498

Gnomad OTH AF: 0.0301

GnomAD3 exomes AF: 0.0404 AC: 10167 AN: 251434 Hom.: 275 AF XY: 0.0424 AC XY: 5761 AN XY: 135888

Gnomad AFR exome AF: 0.0116

Gnomad AMR exome AF: 0.0168

Gnomad ASJ exome AF: 0.0327

Gnomad EAS exome AF: 0.0104

Gnomad SAS exome AF: 0.0454

Gnomad FIN exome AF: 0.0656

Gnomad NFE exome AF: 0.0511

Gnomad OTH exome AF: 0.0415

GnomAD4 exome AF: 0.0480 AC: 70230 AN: 1461626 Hom.: 1895 Cov.: 31 AF XY: 0.0484 AC XY: 35212 AN XY: 727116

Gnomad4 AFR exome AF: 0.0109

Gnomad4 AMR exome AF: 0.0172

Gnomad4 ASJ exome AF: 0.0336

Gnomad4 EAS exome AF: 0.00433

Gnomad4 SAS exome AF: 0.0478

Gnomad4 FIN exome AF: 0.0630

Gnomad4 NFE exome AF: 0.0516

Gnomad4 OTH exome AF: 0.0456

GnomAD4 genome AF: 0.0355 AC: 5399 AN: 152266 Hom.: 121 Cov.: 32 AF XY: 0.0350 AC XY: 2607 AN XY: 74460

Gnomad4 AFR AF: 0.0130

Gnomad4 AMR AF: 0.0244

Gnomad4 ASJ AF: 0.0323

Gnomad4 EAS AF: 0.00676

Gnomad4 SAS AF: 0.0423

Gnomad4 FIN AF: 0.0591

Gnomad4 NFE AF: 0.0498

Gnomad4 OTH AF: 0.0303

Alfa AF: 0.0471 Hom.: 133

Bravo AF: 0.0312

TwinsUK AF: 0.0523 AC: 194

ALSPAC AF: 0.0524 AC: 202

ESP6500AA AF: 0.0127 AC: 56

ESP6500EA AF: 0.0497 AC: 427

ExAC AF: 0.0405 AC: 4915

Asia WGS AF: 0.0200 AC: 68 AN: 3478

EpiCase AF: 0.0514

EpiControl AF: 0.0512

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	T;T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.74	T;T
MetaRNN	Benign	0.0034	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	0.92	D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.057
Sift	Benign	0.032	D;D
Sift4G	Benign	0.10	T;T
Polyphen		0.98	D;.
Vest4		0.22
MPC		0.32
ClinPred		0.017	T
GERP RS		3.5
Varity_R		0.15
gMVP		0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs7084817; hg19: chr10-7774358;