11-78229339-T-C

Variant names:

• chr11-78229339-T-C
• rs2450129
• NM_080491.3:c.621-2288A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_080491.3(GAB2):​c.621-2288A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 151,978 control chromosomes in the GnomAD database, including 3,098 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.19 (3098 hom., cov: 32)
• Consequence: GAB2 NM_080491.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.693
• Publications: 16 publications found

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:20061): (ubiquitin specific peptidase 35) This gene encodes a member of the peptidase C19 family of ubiquitin-specific proteases. These deubiquitinating enzymes (DUBs) catalyze the removal of ubiquitin proteins from other proteins. The encoded protein associates with polarized mitochondria and has been shown to inhibit NF-kappa B activation and delay PARK2-mediated degradation of mitochondria. Expression of this gene is upregulated by the let-7a microRNA and reduced expression has been observed in human tumor tissues. [provided by RefSeq, Jul 2017]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAB2	NM_080491.3	c.621-2288A>G		intron_variant	Intron 3 of 9	ENST00000361507.5	NP_536739.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAB2	ENST00000361507.5	c.621-2288A>G		intron_variant	Intron 3 of 9	1	NM_080491.3	ENSP00000354952.4
GAB2	ENST00000340149.6	c.507-2288A>G		intron_variant	Intron 3 of 9	1		ENSP00000343959.2
GAB2	ENST00000526030.1	n.556-2288A>G		intron_variant	Intron 3 of 3	3
GAB2	ENST00000528329.1	n.125-2288A>G		intron_variant	Intron 1 of 1	4

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29488 AN: 151858 Hom.: 3097 Cov.: 32

Gnomad AFR AF: 0.193

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.182

Gnomad EAS AF: 0.397

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.201

Gnomad MID AF: 0.248

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.203

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.194 AC: 29500 AN: 151978 Hom.: 3098 Cov.: 32 AF XY: 0.198 AC XY: 14671 AN XY: 74278

African (AFR) AF: 0.193 AC: 7992 AN: 41432

American (AMR) AF: 0.249 AC: 3803 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 631 AN: 3470

East Asian (EAS) AF: 0.398 AC: 2049 AN: 5152

South Asian (SAS) AF: 0.281 AC: 1353 AN: 4808

European-Finnish (FIN) AF: 0.201 AC: 2125 AN: 10556

Middle Eastern (MID) AF: 0.257 AC: 75 AN: 292

European-Non Finnish (NFE) AF: 0.162 AC: 10989 AN: 67968

Other (OTH) AF: 0.201 AC: 422 AN: 2104

Alfa AF: 0.177 Hom.: 1409

Bravo AF: 0.197

Asia WGS AF: 0.274 AC: 952 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.79
DANN	Benign	0.79
PhyloP100		-0.69
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2450129; hg19: chr11-77940385;