11-78226549-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_080491.3(GAB2):ā€‹c.1123A>Gā€‹(p.Ile375Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 1,412,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000028 ( 0 hom., cov: 30)
Exomes š‘“: 0.000046 ( 0 hom. )

Consequence

GAB2
NM_080491.3 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.104
Variant links:
Genes affected
GAB2 (HGNC:14458): (GRB2 associated binding protein 2) This gene is a member of the GRB2-associated binding protein (GAB) gene family. These proteins contain pleckstrin homology (PH) domain, and bind SHP2 tyrosine phosphatase and GRB2 adapter protein. They act as adapters for transmitting various signals in response to stimuli through cytokine and growth factor receptors, and T- and B-cell antigen receptors. The protein encoded by this gene is the principal activator of phosphatidylinositol-3 kinase in response to activation of the high affinity IgE receptor. Two alternatively spliced transcripts encoding different isoforms have been described for this gene. [provided by RefSeq, Nov 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0047379136).
BS2
High AC in GnomAdExome4 at 59 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GAB2NM_080491.3 linkuse as main transcriptc.1123A>G p.Ile375Val missense_variant 4/10 ENST00000361507.5 NP_536739.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GAB2ENST00000361507.5 linkuse as main transcriptc.1123A>G p.Ile375Val missense_variant 4/101 NM_080491.3 ENSP00000354952 P1Q9UQC2-1
GAB2ENST00000340149.6 linkuse as main transcriptc.1009A>G p.Ile337Val missense_variant 4/101 ENSP00000343959 Q9UQC2-2

Frequencies

GnomAD3 genomes
AF:
0.0000282
AC:
4
AN:
141748
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.0000255
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000488
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000154
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000107
AC:
27
AN:
251360
Hom.:
0
AF XY:
0.0000957
AC XY:
13
AN XY:
135870
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00130
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000464
AC:
59
AN:
1270258
Hom.:
0
Cov.:
34
AF XY:
0.0000428
AC XY:
27
AN XY:
630282
show subpopulations
Gnomad4 AFR exome
AF:
0.0000359
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00216
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000111
Gnomad4 OTH exome
AF:
0.0000210
GnomAD4 genome
AF:
0.0000282
AC:
4
AN:
141886
Hom.:
0
Cov.:
30
AF XY:
0.0000145
AC XY:
1
AN XY:
68890
show subpopulations
Gnomad4 AFR
AF:
0.0000254
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000488
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000154
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000189
ExAC
AF:
0.000115
AC:
14
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 22, 2023The c.1123A>G (p.I375V) alteration is located in exon 4 (coding exon 4) of the GAB2 gene. This alteration results from a A to G substitution at nucleotide position 1123, causing the isoleucine (I) at amino acid position 375 to be replaced by a valine (V). 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
0.053
BayesDel_addAF
Benign
-0.70
T
BayesDel_noAF
Benign
-0.81
CADD
Benign
0.036
DANN
Benign
0.45
DEOGEN2
Benign
0.26
.;T
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.048
N
LIST_S2
Benign
0.12
T;T
M_CAP
Benign
0.0026
T
MetaRNN
Benign
0.0047
T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
-0.99
.;N
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.27
T
PROVEAN
Benign
0.38
N;N
REVEL
Benign
0.054
Sift
Benign
0.31
T;T
Sift4G
Benign
0.53
T;T
Polyphen
0.0
.;B
Vest4
0.048
MutPred
0.056
.;Gain of MoRF binding (P = 0.1268);
MVP
0.14
MPC
0.046
ClinPred
0.017
T
GERP RS
-3.5
Varity_R
0.016
gMVP
0.096

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

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

Other links and lift over

dbSNP: rs546063891; hg19: chr11-77937595; API