rs869312825

Variant names:

• chr1-1804548-T-C
• rs869312825
• NM_002074.5:c.301A>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001282538.2(GNB1):​c.1A>G​(p.Met1?) variant causes a start lost 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNB1 NM_001282538.2 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 7.84
• Publications: 5 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 18 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 14 pathogenic variants. Next in-frame start position is after 88 codons. Genomic position: 1790532. Lost 0.362 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-1804548-T-C is Pathogenic according to our data. Variant chr1-1804548-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 224717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001282538.2. 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.301A>G	p.Met101Val	missense	Exon 7 of 12	NP_002065.1	P62873-1
	GNB1	NM_001282538.2		c.1A>G	p.Met1?	start_lost	Exon 5 of 10	NP_001269467.1	B3KVK2
	GNB1	NM_001282539.2		c.301A>G	p.Met101Val	missense	Exon 6 of 11	NP_001269468.1	A0A140VJJ8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNB1	ENST00000378609.9	TSL:1 MANE Select	c.301A>G	p.Met101Val	missense	Exon 7 of 12	ENSP00000367872.3	P62873-1
	GNB1	ENST00000615252.5	TSL:5	c.1A>G	p.Met1?	start_lost	Exon 4 of 9	ENSP00000483532.1	B3KVK2
	GNB1	ENST00000947520.1		c.301A>G	p.Met101Val	missense	Exon 7 of 13	ENSP00000617579.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Intellectual disability, autosomal dominant 42 (5)
2	-	-	not provided (2)
1	-	-	Hypotonia;C0036572:Seizure;C0270834:Focal impaired awareness seizure;C0454641:Expressive language delay;C0494475:Bilateral tonic-clonic seizure;C0557874:Global developmental delay;C1836830:Developmental regression;C3714756:Intellectual disability;C4021219:Multifocal epileptiform discharges;C4023476:EEG with generalized epileptiform discharges (1)
1	-	-	Hypotonia;C0036572:Seizure;na:Neurodevelopmental Disability (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	0.25
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.31	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.023	D
Polyphen		0.52	P
Vest4		0.90
MutPred		0.63		Loss of catalytic residue at M101 (P = 0.0833)
MVP		0.93
MPC		2.4
ClinPred		0.98	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.61
Mutation Taster		=7/93	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: rs869312825; hg19: chr1-1735987; COSMIC: COSV108221601;