rs758432471

Positions:

• chr1-1806513-C-A
• chr1-1806513-C-G
• chr1-1806513-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_002074.5(GNB1):​c.229G>T​(p.Gly77Cys) 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. G77A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNB1 NM_002074.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.71

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]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a turn (size 2) in uniprot entity GBB1_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) 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 chr1-1806512-C-G is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GNB1. . Gene score misZ 3.8328 (greater than the threshold 3.09). Trascript score misZ 3.4817 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 42.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915
• PP5: Variant 1-1806513-C-A is Pathogenic according to our data. Variant chr1-1806513-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1700090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNB1	NM_002074.5	c.229G>T	p.Gly77Cys	missense_variant	6/12	ENST00000378609.9	NP_002065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNB1	ENST00000378609.9	c.229G>T	p.Gly77Cys	missense_variant	6/12	1	NM_002074.5	ENSP00000367872	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental delay Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

-

- -

Intellectual disability, autosomal dominant 42 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	32
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.47	T;T;T;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;.;D;D;D
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	1.5	L;L;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.7	.;D;D;D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.014	.;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;.;.;.
Polyphen		1.0	D;D;.;.;.
Vest4		0.90
MutPred		0.76		Gain of methylation at K78 (P = 0.0314);Gain of methylation at K78 (P = 0.0314);.;Gain of methylation at K78 (P = 0.0314);Gain of methylation at K78 (P = 0.0314);
MVP		0.96
MPC		3.1
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.97
gMVP		0.90

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-1737952; COSMIC: COSV101060808;