1-1806512-C-G

Variant names:

• chr1-1806512-C-G
• rs1135401746
• NM_002074.5:c.230G>C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 PM1 PM2 PM5 PP3_Moderate PP5

The NM_002074.5(GNB1):​c.230G>C​(p.Gly77Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000574520: These GNB1mutations may be actionable as in vivo administration of a small molecule inhibitor of the PI3K and mTOR pathways were shown to improve the survival of mice with GNB1-induced myeloid leukaemia [Yoda et al., 2015].". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G77C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: GNB1 NM_002074.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 7.71
• Publications: 3 publications found

Genes affected

GNB1 (HGNC:4396): (G protein subunit beta 1) Heterotrimeric guanine nucleotide-binding proteins (G proteins), which integrate signals between receptors and effector proteins, are composed of an alpha, a beta, and a gamma subunit. These subunits are encoded by families of related genes. This gene encodes a beta subunit. Beta subunits are important regulators of alpha subunits, as well as of certain signal transduction receptors and effectors. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

GNB1 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal dominant 42

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Illumina, ClinGen, G2P, Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000574520: These GNB1mutations may be actionable as in vivo administration of a small molecule inhibitor of the PI3K and mTOR pathways were shown to improve the survival of mice with GNB1-induced myeloid leukaemia [Yoda et al., 2015].
• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_002074.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-1806513-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1700090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903
• PP5: Variant 1-1806512-C-G is Pathogenic according to our data. Variant chr1-1806512-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 431082.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002074.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNB1	NM_002074.5	MANE Select	c.230G>C	p.Gly77Ala	missense	Exon 6 of 12	NP_002065.1	P62873-1
	GNB1	NM_001282539.2		c.230G>C	p.Gly77Ala	missense	Exon 5 of 11	NP_001269468.1	A0A140VJJ8
	GNB1	NM_001282538.2		c.-71G>C		5_prime_UTR	Exon 4 of 10	NP_001269467.1	B3KVK2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNB1	ENST00000378609.9	TSL:1 MANE Select	c.230G>C	p.Gly77Ala	missense	Exon 6 of 12	ENSP00000367872.3	P62873-1
	GNB1	ENST00000947520.1		c.230G>C	p.Gly77Ala	missense	Exon 6 of 13	ENSP00000617579.1
	GNB1	ENST00000947524.1		c.230G>C	p.Gly77Ala	missense	Exon 6 of 13	ENSP00000617583.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	Intellectual disability, autosomal dominant 42 (2)
2	-	-	not provided (2)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.071	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	1.5	L
PhyloP100		7.7
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.98	D
Vest4		0.82
MutPred		0.75		Loss of ubiquitination at K78 (P = 0.1099)
MVP		0.94
MPC		3.1
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.81
Mutation Taster		=6/94	disease causing (ClinVar)

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: rs1135401746; hg19: chr1-1737951;