NM_002203.4:c.1600G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002203.4(ITGA2):​c.1600G>A​(p.Glu534Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0901 in 1,598,154 control chromosomes in the GnomAD database, including 7,290 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 1140 hom., cov: 32)
Exomes 𝑓: 0.088 ( 6150 hom. )

Consequence

ITGA2
NM_002203.4 missense, splice_region

Scores

15
Splicing: ADA: 0.00001115
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.00

Publications

28 publications found
Variant links:
Genes affected
ITGA2 (HGNC:6137): (integrin subunit alpha 2) This gene encodes the alpha subunit of a transmembrane receptor for collagens and related proteins. The encoded protein forms a heterodimer with a beta subunit and mediates the adhesion of platelets and other cell types to the extracellular matrix. Loss of the encoded protein is associated with bleeding disorder platelet-type 9. Antibodies against this protein are found in several immune disorders, including neonatal alloimmune thrombocytopenia. This gene is located adjacent to a related alpha subunit gene. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]
ITGA2 Gene-Disease associations (from GenCC):
  • platelet-type bleeding disorder 9
    Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0011746883).
BP6
Variant 5-53062927-G-A is Benign according to our data. Variant chr5-53062927-G-A is described in CliVar as Benign. Clinvar id is 353753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-53062927-G-A is described in CliVar as Benign. Clinvar id is 353753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-53062927-G-A is described in CliVar as Benign. Clinvar id is 353753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ITGA2NM_002203.4 linkc.1600G>A p.Glu534Lys missense_variant, splice_region_variant Exon 13 of 30 ENST00000296585.10 NP_002194.2 P17301

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ITGA2ENST00000296585.10 linkc.1600G>A p.Glu534Lys missense_variant, splice_region_variant Exon 13 of 30 1 NM_002203.4 ENSP00000296585.5 P17301

Frequencies

GnomAD3 genomes
AF:
0.113
AC:
16833
AN:
149358
Hom.:
1132
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.187
Gnomad AMI
AF:
0.0385
Gnomad AMR
AF:
0.0850
Gnomad ASJ
AF:
0.112
Gnomad EAS
AF:
0.0269
Gnomad SAS
AF:
0.0873
Gnomad FIN
AF:
0.0587
Gnomad MID
AF:
0.159
Gnomad NFE
AF:
0.0903
Gnomad OTH
AF:
0.124
GnomAD2 exomes
AF:
0.0856
AC:
20898
AN:
244036
AF XY:
0.0867
show subpopulations
Gnomad AFR exome
AF:
0.190
Gnomad AMR exome
AF:
0.0597
Gnomad ASJ exome
AF:
0.114
Gnomad EAS exome
AF:
0.0193
Gnomad FIN exome
AF:
0.0540
Gnomad NFE exome
AF:
0.0914
Gnomad OTH exome
AF:
0.0961
GnomAD4 exome
AF:
0.0877
AC:
127055
AN:
1448680
Hom.:
6150
Cov.:
31
AF XY:
0.0883
AC XY:
63645
AN XY:
720734
show subpopulations
African (AFR)
AF:
0.193
AC:
6340
AN:
32862
American (AMR)
AF:
0.0621
AC:
2712
AN:
43658
Ashkenazi Jewish (ASJ)
AF:
0.115
AC:
2968
AN:
25796
East Asian (EAS)
AF:
0.0338
AC:
1330
AN:
39324
South Asian (SAS)
AF:
0.0896
AC:
7600
AN:
84826
European-Finnish (FIN)
AF:
0.0531
AC:
2814
AN:
52982
Middle Eastern (MID)
AF:
0.153
AC:
870
AN:
5680
European-Non Finnish (NFE)
AF:
0.0876
AC:
96716
AN:
1103902
Other (OTH)
AF:
0.0956
AC:
5705
AN:
59650
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.466
Heterozygous variant carriers
0
4898
9796
14693
19591
24489
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
3536
7072
10608
14144
17680
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.113
AC:
16880
AN:
149474
Hom.:
1140
Cov.:
32
AF XY:
0.109
AC XY:
7943
AN XY:
72770
show subpopulations
African (AFR)
AF:
0.188
AC:
7670
AN:
40796
American (AMR)
AF:
0.0849
AC:
1277
AN:
15046
Ashkenazi Jewish (ASJ)
AF:
0.112
AC:
386
AN:
3448
East Asian (EAS)
AF:
0.0269
AC:
136
AN:
5048
South Asian (SAS)
AF:
0.0873
AC:
415
AN:
4756
European-Finnish (FIN)
AF:
0.0587
AC:
576
AN:
9820
Middle Eastern (MID)
AF:
0.168
AC:
49
AN:
292
European-Non Finnish (NFE)
AF:
0.0903
AC:
6077
AN:
67290
Other (OTH)
AF:
0.125
AC:
259
AN:
2068
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.510
Heterozygous variant carriers
0
755
1510
2266
3021
3776
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
182
364
546
728
910
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0938
Hom.:
2661
Bravo
AF:
0.117
TwinsUK
AF:
0.0903
AC:
335
ALSPAC
AF:
0.0919
AC:
354
ESP6500AA
AF:
0.181
AC:
799
ESP6500EA
AF:
0.0957
AC:
823
ExAC
AF:
0.0875
AC:
10605
Asia WGS
AF:
0.0890
AC:
308
AN:
3470

ClinVar

Significance: Benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Jun 10, 2021
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22133774, 7901236, 10744142) -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Platelet-type bleeding disorder 9 Benign:1
Mar 06, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.065
BayesDel_addAF
Benign
-0.67
T
BayesDel_noAF
Benign
-0.66
CADD
Benign
12
DANN
Benign
0.83
Eigen
Benign
0.00062
Eigen_PC
Benign
0.025
FATHMM_MKL
Benign
0.38
N
MetaRNN
Benign
0.0012
T
MetaSVM
Benign
-0.94
T
PhyloP100
3.0
PrimateAI
Benign
0.39
T
PROVEAN
Benign
0.59
N
REVEL
Benign
0.057
Sift
Benign
0.88
T
Sift4G
Benign
1.0
T
Vest4
0.044
MPC
0.19
ClinPred
0.0059
T
GERP RS
4.8
gMVP
0.54
Mutation Taster
=96/4
polymorphism (auto)

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000011
dbscSNV1_RF
Benign
0.0
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

Other links and lift over

dbSNP: rs1801106; hg19: chr5-52358757; API