11-78226722-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_080491.3(GAB2):c.950C>T(p.Pro317Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,613,908 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00093 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0010 (17 hom.)
• Consequence: GAB2 NM_080491.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.27

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009805918).
• BP6: Variant 11-78226722-G-A is Benign according to our data. Variant chr11-78226722-G-A is described in ClinVar as [Benign]. Clinvar id is 718663.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-78226722-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00103 (1512/1461764) while in subpopulation EAS AF= 0.0259 (1028/39700). AF 95% confidence interval is 0.0246. There are 17 homozygotes in gnomad4_exome. There are 717 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High AC in GnomAd at 141 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAB2	NM_080491.3	c.950C>T	p.Pro317Leu	missense_variant	4/10	ENST00000361507.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAB2	ENST00000361507.5	c.950C>T	p.Pro317Leu	missense_variant	4/10	1	NM_080491.3	P1
GAB2	ENST00000340149.6	c.836C>T	p.Pro279Leu	missense_variant	4/10	1
GAB2	ENST00000528329.1	n.454C>T		non_coding_transcript_exon_variant	2/2	4

Frequencies

GnomAD3 genomes AF: 0.000927 AC: 141 AN: 152026 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0168

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00216 AC: 543 AN: 251378 Hom.: 5 AF XY: 0.00190 AC XY: 258 AN XY: 135868

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00711

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0153

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00103 AC: 1512 AN: 1461764 Hom.: 17 Cov.: 35 AF XY: 0.000986 AC XY: 717 AN XY: 727198

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00702

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0259

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000585

Gnomad4 OTH exome AF: 0.00161

GnomAD4 genome AF: 0.000927 AC: 141 AN: 152144 Hom.: 4 Cov.: 31 AF XY: 0.000941 AC XY: 70 AN XY: 74390

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0168

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000791 Hom.: 0

Bravo AF: 0.00145

ExAC AF: 0.00198 AC: 240

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 20, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.050
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D;D
MetaRNN	Benign	0.0098	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.012	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	.;D
Vest4		0.83
MVP		0.78
MPC		0.34
ClinPred		0.079	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.53

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: rs116286425; hg19: chr11-77937768; COSMIC: COSV60871315; COSMIC: COSV60871315;