rs869312821

Variant names:

• chr1-1806515-T-C
• rs869312821
• NM_002074.5:c.227A>G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_002074.5(GNB1):​c.227A>G​(p.Asp76Gly) 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. 13/22 in silico tools predict a damaging 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. D76E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNB1 NM_002074.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.82
• Publications: 8 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 16 ACMG points.

• PM1: In a hotspot region, there are 12 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 chr1-1806514-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 224712.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92
• PP5: Variant 1-1806515-T-C is Pathogenic according to our data. Variant chr1-1806515-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 224711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.227A>G	p.Asp76Gly	missense	Exon 6 of 12	NP_002065.1	P62873-1
	GNB1	NM_001282539.2		c.227A>G	p.Asp76Gly	missense	Exon 5 of 11	NP_001269468.1	A0A140VJJ8
	GNB1	NM_001282538.2		c.-74A>G		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.227A>G	p.Asp76Gly	missense	Exon 6 of 12	ENSP00000367872.3	P62873-1
	GNB1	ENST00000947520.1		c.227A>G	p.Asp76Gly	missense	Exon 6 of 13	ENSP00000617579.1
	GNB1	ENST00000947524.1		c.227A>G	p.Asp76Gly	missense	Exon 6 of 13	ENSP00000617583.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Acute lymphoid leukemia (1)
1	-	-	Hypotonia;C0036572:Seizure;na:Neurodevelopmental Disability (1)
1	-	-	Hypotonia;C0557874:Global developmental delay;C1860834:Floppy infant;C3714756:Intellectual disability (1)
1	-	-	Intellectual disability, autosomal dominant 42 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
PhyloP100		7.8
Varity_R		0.98
gMVP		0.98
Mutation Taster		=3/97	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs869312821; hg19: chr1-1737954; COSMIC: COSV66099716;