Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS1PM1PM2PM5PP3_ModeratePP5_Moderate

The NM_002074.5(GNB1):c.228T>A(p.Asp76Glu) variant causes a missense change involving the alteration of a non-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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D76N) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

GNB1
NM_002074.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.55

Publications

0 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 14 ACMG points.

PS1

Transcript NM_002074.5 (GNB1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

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 chr1-1806516-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 976696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.879

PP5

Variant 1-1806514-A-T is Pathogenic according to our data. Variant chr1-1806514-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1699320.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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GNB1	NM_002074.5	MANE Select	c.228T>A	p.Asp76Glu	missense	Exon 6 of 12	NP_002065.1
GNB1	NM_001282539.2		c.228T>A	p.Asp76Glu	missense	Exon 5 of 11	NP_001269468.1
GNB1	NM_001282538.2		c.-73T>A		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.228T>A	p.Asp76Glu	missense	Exon 6 of 12	ENSP00000367872.3
GNB1	ENST00000610897.4	TSL:5	c.228T>A	p.Asp76Glu	missense	Exon 5 of 11	ENSP00000481878.1
GNB1	ENST00000703692.1		c.228T>A	p.Asp76Glu	missense	Exon 6 of 11	ENSP00000515427.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Intellectual disability, autosomal dominant 42 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.41

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.88

MetaSVM

Uncertain

0.46

MutationAssessor

Pathogenic

3.1

PhyloP100

2.6

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.6

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

0.87

Vest4

0.98

MutPred

0.76

Gain of methylation at K78 (P = 0.0963)

MVP

0.98

MPC

2.0

ClinPred

0.99

GERP RS

0.76

Varity_R

0.94

gMVP

0.96

Mutation Taster

=7/93

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over