dbSNP rs869312823: GNB1:p.Lys78Arg (chr1-1806509-T-C) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong

The NM_002074.5(GNB1):c.233A>G(p.Lys78Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 31)

Consequence

GNB1
NM_002074.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15O:2

Conservation

PhyloP100: 7.82

Publications

10 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina, G2P

GNB1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM1

In a hotspot region, there are 15 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;

PP5

Variant 1-1806509-T-C is Pathogenic according to our data. Variant chr1-1806509-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 224714.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
GNB1	NM_002074.5	MANE Select	c.233A>G	p.Lys78Arg	missense	Exon 6 of 12	NP_002065.1
GNB1	NM_001282539.2		c.233A>G	p.Lys78Arg	missense	Exon 5 of 11	NP_001269468.1
GNB1	NM_001282538.2		c.-68A>G		5_prime_UTR	Exon 4 of 10	NP_001269467.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GNB1	ENST00000378609.9	TSL:1 MANE Select	c.233A>G	p.Lys78Arg	missense	Exon 6 of 12	ENSP00000367872.3
GNB1	ENST00000947520.1		c.233A>G	p.Lys78Arg	missense	Exon 6 of 13	ENSP00000617579.1
GNB1	ENST00000947524.1		c.233A>G	p.Lys78Arg	missense	Exon 6 of 13	ENSP00000617583.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Intellectual disability, autosomal dominant 42 (10)

not provided (3)

Hypotonia;C0036572:Seizure;C0038379:Strabismus;C0232466:Feeding difficulties;C0456070:Growth delay;C0557874:Global developmental delay;C1860834:Floppy infant;C4023476:EEG with generalized epileptiform discharges (1)

Hypotonia;C0036572:Seizure;na:Neurodevelopmental Disability (1)

Inborn genetic diseases (1)

GNB1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Benign

0.0040

BayesDel_noAF

Benign

-0.23

CADD

Pathogenic

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.38

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.024

MetaRNN

Uncertain

0.53

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.28

PhyloP100

7.8

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.31

Sift

Benign

0.053

Sift4G

Benign

0.20

Polyphen

0.85

Vest4

0.87

MutPred

0.47

Loss of methylation at K78 (P = 0.0179)

MVP

0.72

MPC

2.4

ClinPred

0.96

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.74

gMVP

0.64

Mutation Taster

=18/82

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