7-100676751-G-A

Variant names:

• chr7-100676751-G-A
• rs948934468
• NM_005273.4:c.155G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_005273.4(GNB2):​c.155G>A​(p.Arg52His) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R52L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GNB2 NM_005273.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.16

Genes affected

GNB2 (HGNC:4398): (G protein subunit beta 2) 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. This gene contains a trinucleotide (CCG) repeat length polymorphism in its 5' UTR. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-100676751-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1185051.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNB2	NM_005273.4	c.155G>A	p.Arg52His	missense_variant	Exon 4 of 10	ENST00000303210.9	NP_005264.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNB2	ENST00000303210.9	c.155G>A	p.Arg52His	missense_variant	Exon 4 of 10	1	NM_005273.4	ENSP00000305260.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 52 of the GNB2 protein (p.Arg52His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GNB2-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt GNB2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.19	T;.;T;T;T;T;.;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.84	.;T;.;T;.;T;D;T
M_CAP	Benign	0.077	D
MetaRNN	Uncertain	0.68	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.93	L;.;.;.;L;.;.;L
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.6	D;D;D;D;D;D;D;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.019	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;D;.;.;D
Vest4		0.44
MutPred		0.55		Loss of methylation at R52 (P = 0.0241);Loss of methylation at R52 (P = 0.0241);.;.;Loss of methylation at R52 (P = 0.0241);Loss of methylation at R52 (P = 0.0241);Loss of methylation at R52 (P = 0.0241);Loss of methylation at R52 (P = 0.0241);
MVP		0.59
MPC		1.8
ClinPred		0.96	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.39
gMVP		0.70

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

LitVar

Other links and lift over

dbSNP: rs948934468; hg19: chr7-100274374; COSMIC: COSV51944458; COSMIC: COSV51944458;