10-7720938-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002216.3(ITIH2):​c.713C>T​(p.Pro238Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000416 in 1,612,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

ITIH2
NM_002216.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.86
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.18187445).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ITIH2NM_002216.3 linkc.713C>T p.Pro238Leu missense_variant Exon 7 of 21 ENST00000358415.9 NP_002207.2 P19823

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ITIH2ENST00000358415.9 linkc.713C>T p.Pro238Leu missense_variant Exon 7 of 21 1 NM_002216.3 ENSP00000351190.4 P19823
ITIH2ENST00000379587.4 linkc.680C>T p.Pro227Leu missense_variant Exon 6 of 20 5 ENSP00000368906.3 Q5T985
ITIH2ENST00000429820.5 linkc.638C>T p.Pro213Leu missense_variant Exon 6 of 7 3 ENSP00000388826.1 Q5T987
ITIH2ENST00000480387.1 linkn.*37C>T downstream_gene_variant 3

Frequencies

GnomAD3 genomes
AF:
0.0000592
AC:
9
AN:
152094
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000208
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000557
AC:
14
AN:
251464
Hom.:
0
AF XY:
0.0000589
AC XY:
8
AN XY:
135912
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.000163
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000528
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000397
AC:
58
AN:
1460014
Hom.:
0
Cov.:
29
AF XY:
0.0000441
AC XY:
32
AN XY:
726426
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000151
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000351
Gnomad4 OTH exome
AF:
0.0000332
GnomAD4 genome
AF:
0.0000592
AC:
9
AN:
152094
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74284
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000491
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.0000412
AC:
5
Asia WGS
AF:
0.00115
AC:
4
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
May 28, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.713C>T (p.P238L) alteration is located in exon 7 (coding exon 7) of the ITIH2 gene. This alteration results from a C to T substitution at nucleotide position 713, causing the proline (P) at amino acid position 238 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.48
CADD
Benign
18
DANN
Benign
0.77
DEOGEN2
Benign
0.014
T;T;T
Eigen
Benign
0.043
Eigen_PC
Benign
0.079
FATHMM_MKL
Benign
0.44
N
LIST_S2
Uncertain
0.93
D;D;D
M_CAP
Benign
0.0070
T
MetaRNN
Benign
0.18
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.1
L;.;.
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-1.5
N;N;N
REVEL
Benign
0.15
Sift
Benign
0.40
T;T;T
Sift4G
Benign
0.67
T;T;T
Polyphen
0.77
P;.;.
Vest4
0.42
MutPred
0.55
Gain of sheet (P = 0.0344);.;.;
MVP
0.57
MPC
0.089
ClinPred
0.070
T
GERP RS
5.3
Varity_R
0.061
gMVP
0.35

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs551693398; hg19: chr10-7762901; COSMIC: COSV64432040; COSMIC: COSV64432040; API