11-78232411-T-G

Variant names:

• chr11-78232411-T-G
• rs2450130
• NM_080491.3:c.621-5360A>C

Variant summary

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

The NM_080491.3(GAB2):​c.621-5360A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 152,132 control chromosomes in the GnomAD database, including 3,109 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 (3109 hom., cov: 32)
• Consequence: GAB2 NM_080491.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.346
• Publications: 15 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=-0.75).
• 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.621-5360A>C		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.621-5360A>C		intron_variant	Intron 3 of 9	1	NM_080491.3	ENSP00000354952.4
GAB2	ENST00000340149.6	c.507-5360A>C		intron_variant	Intron 3 of 9	1		ENSP00000343959.2
GAB2	ENST00000526030.1	n.556-5360A>C		intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29580 AN: 152014 Hom.: 3107 Cov.: 32

Gnomad AFR AF: 0.193

Gnomad AMI AF: 0.0670

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.194

Gnomad EAS AF: 0.396

Gnomad SAS AF: 0.280

Gnomad FIN AF: 0.201

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.204

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

GnomAD4 genome AF: 0.195 AC: 29593 AN: 152132 Hom.: 3109 Cov.: 32 AF XY: 0.198 AC XY: 14710 AN XY: 74360

African (AFR) AF: 0.193 AC: 7993 AN: 41510

American (AMR) AF: 0.248 AC: 3796 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 672 AN: 3470

East Asian (EAS) AF: 0.397 AC: 2050 AN: 5162

South Asian (SAS) AF: 0.280 AC: 1348 AN: 4822

European-Finnish (FIN) AF: 0.201 AC: 2128 AN: 10580

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.162 AC: 11045 AN: 67990

Other (OTH) AF: 0.201 AC: 425 AN: 2110

Alfa AF: 0.194 Hom.: 873

Bravo AF: 0.198

Asia WGS AF: 0.275 AC: 953 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	10
DANN	Benign	0.84
PhyloP100		0.35
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: rs2450130; hg19: chr11-77943457;