rs1135401746

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr1-1806512-C-A
• chr1-1806512-C-G
• chr1-1806512-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_002074.5(GNB1):​c.230G>T​(p.Gly77Val) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G77A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: GNB1 NM_002074.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.71
• Publications: 1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• 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 chr1-1806512-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 431082.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93
• PP5: Variant 1-1806512-C-A is Pathogenic according to our data. Variant chr1-1806512-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1315582.Status of the report is criteria_provided_single_submitter, 1 stars.

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>T	p.Gly77Val	missense	Exon 6 of 12	NP_002065.1
	GNB1	NM_001282539.2		c.230G>T	p.Gly77Val	missense	Exon 5 of 11	NP_001269468.1
	GNB1	NM_001282538.2		c.-71G>T		5_prime_UTR	Exon 4 of 10	NP_001269467.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNB1	ENST00000378609.9	TSL:1 MANE Select	c.230G>T	p.Gly77Val	missense	Exon 6 of 12	ENSP00000367872.3
	GNB1	ENST00000947520.1		c.230G>T	p.Gly77Val	missense	Exon 6 of 13	ENSP00000617579.1
	GNB1	ENST00000947524.1		c.230G>T	p.Gly77Val	missense	Exon 6 of 13	ENSP00000617583.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	31
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.51	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.7
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-8.0	D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.021	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.75		Gain of methylation at K78 (P = 0.0562)
MVP		0.94
MPC		3.4
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.91
Mutation Taster		=8/92	disease causing

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;