11-78222097-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_080491.3(GAB2):c.1658+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,577,812 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (7 hom.)
• Consequence: GAB2 NM_080491.3 splice_region, intron
• Scores: Splicing: ADA: 0.00004840
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.642

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 11-78222097-G-A is Benign according to our data. Variant chr11-78222097-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 722439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 214 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAB2	NM_080491.3	c.1658+8C>T		splice_region_variant, intron_variant		ENST00000361507.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAB2	ENST00000361507.5	c.1658+8C>T		splice_region_variant, intron_variant		1	NM_080491.3	P1
GAB2	ENST00000340149.6	c.1544+8C>T		splice_region_variant, intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 214 AN: 152068 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00397

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00182

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00126 AC: 317 AN: 251344 Hom.: 1 AF XY: 0.00124 AC XY: 169 AN XY: 135850

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00425

Gnomad NFE exome AF: 0.00166

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00123 AC: 1760 AN: 1425626 Hom.: 7 Cov.: 26 AF XY: 0.00124 AC XY: 885 AN XY: 711714

Gnomad4 AFR exome AF: 0.0000610

Gnomad4 AMR exome AF: 0.000627

Gnomad4 ASJ exome AF: 0.0000386

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000129

Gnomad4 FIN exome AF: 0.00371

Gnomad4 NFE exome AF: 0.00134

Gnomad4 OTH exome AF: 0.00117

GnomAD4 genome AF: 0.00141 AC: 214 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.00163 AC XY: 121 AN XY: 74396

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00397

Gnomad4 NFE AF: 0.00182

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00148 Hom.: 0

Bravo AF: 0.00118

EpiCase AF: 0.00153

EpiControl AF: 0.00113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	GAB2: BP4 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jun 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	4.4
Dann	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000048
dbscSNV1_RF	Benign	0.0060
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: rs201950264; hg19: chr11-77933143; COSMIC: COSV104413179; COSMIC: COSV104413179;