11-78226506-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_080491.3(GAB2):c.1166G>A(p.Arg389His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,032 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GAB2 NM_080491.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.46

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]

USP35 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAB2	NM_080491.3	c.1166G>A	p.Arg389His	missense_variant	4/10	ENST00000361507.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAB2	ENST00000361507.5	c.1166G>A	p.Arg389His	missense_variant	4/10	1	NM_080491.3	P1
GAB2	ENST00000340149.6	c.1052G>A	p.Arg351His	missense_variant	4/10	1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460032 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726312

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2022

The c.1166G>A (p.R389H) alteration is located in exon 4 (coding exon 4) of the GAB2 gene. This alteration results from a G to A substitution at nucleotide position 1166, causing the arginine (R) at amino acid position 389 to be replaced by a histidine (H). 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	Pathogenic	0.63
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Benign	-0.70	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.18
Sift	Uncertain	0.019	D;D
Sift4G	Uncertain	0.045	D;D
Polyphen		1.0	.;D
Vest4		0.81
MutPred		0.17		.;Loss of MoRF binding (P = 0.0156);
MVP		0.55
MPC		0.093
ClinPred		0.92	D
GERP RS		5.2
Varity_R		0.49
gMVP		0.41

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: rs1319380309; hg19: chr11-77937552;