22-29639142-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_000268.4(NF2):​c.293C>G​(p.Ala98Gly) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A98D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Consequence

NF2
NM_000268.4 missense

Scores

6
12
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.81
Variant links:
Genes affected
NF2 (HGNC:7773): (NF2, moesin-ezrin-radixin like (MERLIN) tumor suppressor) This gene encodes a protein that is similar to some members of the ERM (ezrin, radixin, moesin) family of proteins that link cytoskeletal components with proteins in the cell membrane. The encoded protein is involved in regulation of contact-dependent inhibition of cell proliferation and functions in cell-cell adhesion and transmembrane signaling. The encoded protein has been shown to interact with cell-surface proteins, proteins involved in cytoskeletal dynamics, and proteins involved in regulating ion transport. Disruption of this protein's function has been implicated in tumorigenesis and metastasis. Mutations in this gene are associated with neurofibromatosis type II which is characterized by nervous system and skin tumors and ocular abnormalities. [provided by RefSeq, May 2022]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.83

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NF2NM_000268.4 linkuse as main transcriptc.293C>G p.Ala98Gly missense_variant 3/16 ENST00000338641.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NF2ENST00000338641.10 linkuse as main transcriptc.293C>G p.Ala98Gly missense_variant 3/161 NM_000268.4 P1P35240-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.54
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Uncertain
-0.020
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.82
.;D;.;.;.;.;.
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.60
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D;D;D;.;.;D;D
M_CAP
Uncertain
0.29
D
MetaRNN
Pathogenic
0.83
D;D;D;D;D;D;D
MetaSVM
Uncertain
0.72
D
MutationAssessor
Pathogenic
3.0
M;M;M;M;M;.;M
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
0.85
D
PROVEAN
Uncertain
-3.8
D;D;D;D;D;D;D
REVEL
Pathogenic
0.77
Sift
Uncertain
0.0030
D;D;D;D;D;D;D
Sift4G
Uncertain
0.015
D;D;D;D;D;D;D
Polyphen
0.99
D;D;.;D;D;D;D
Vest4
0.73
MutPred
0.65
Loss of stability (P = 0.0241);Loss of stability (P = 0.0241);Loss of stability (P = 0.0241);Loss of stability (P = 0.0241);Loss of stability (P = 0.0241);.;Loss of stability (P = 0.0241);
MVP
0.91
MPC
1.7
ClinPred
0.99
D
GERP RS
4.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.84
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-30035131; API