7-100676747-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_005273.4(GNB2):​c.151C>A​(p.Leu51Ile) variant causes a missense change. 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

GNB2
NM_005273.4 missense

Scores

7
8
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.15
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_005273.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.877

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GNB2NM_005273.4 linkc.151C>A p.Leu51Ile missense_variant Exon 4 of 10 ENST00000303210.9 NP_005264.2 P62879-1Q6FHM2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GNB2ENST00000303210.9 linkc.151C>A p.Leu51Ile missense_variant Exon 4 of 10 1 NM_005273.4 ENSP00000305260.4 P62879-1

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
LINK: link

Submissions by phenotype

not provided Uncertain:1
May 26, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Uncertain
0.061
T
BayesDel_noAF
Benign
-0.15
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Benign
0.11
T;.;T;T;T;T;.;T
Eigen
Pathogenic
0.80
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.99
.;D;.;D;.;D;D;D
M_CAP
Uncertain
0.10
D
MetaRNN
Pathogenic
0.88
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.10
D
MutationAssessor
Uncertain
2.3
M;.;.;.;M;.;.;M
PrimateAI
Pathogenic
0.89
D
PROVEAN
Benign
-1.7
N;N;N;N;N;N;N;N
REVEL
Uncertain
0.48
Sift
Uncertain
0.0010
D;D;D;D;D;D;D;D
Sift4G
Uncertain
0.0040
D;D;D;D;D;D;T;D
Polyphen
0.98
D;.;.;.;D;.;.;D
Vest4
0.69
MutPred
0.80
Loss of methylation at R52 (P = 0.0713);Loss of methylation at R52 (P = 0.0713);.;.;Loss of methylation at R52 (P = 0.0713);Loss of methylation at R52 (P = 0.0713);Loss of methylation at R52 (P = 0.0713);Loss of methylation at R52 (P = 0.0713);
MVP
0.59
MPC
2.5
ClinPred
0.98
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.55
gMVP
0.72

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: chr7-100274370; API