Genetic Variant NM_002074.5:c.301A>G (chr1-1804548-T-C) – ACMG Classification: Pathogenic (14 pts)

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_002074.5(GNB1):c.301A>G(p.Met101Val) 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. M101I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

GNB1
NM_002074.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 7.84

Publications

5 publications found

Variant links:

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

GNB1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_002074.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.846

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_002074.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

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

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.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Intellectual disability, autosomal dominant 42 (5)

not provided (2)

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)

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

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.38

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.83

MetaSVM

Benign

-0.31

MutationAssessor

Pathogenic

3.2

PhyloP100

7.8

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.6

REVEL

Uncertain

0.52

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.023

Polyphen

0.52

Vest4

0.90

MutPred

0.63

Loss of catalytic residue at M101 (P = 0.0833)

MVP

0.93

MPC

2.4

ClinPred

0.98

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)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over