rs1302428933
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000268.4(NF2):c.111C>A(p.Cys37*) variant causes a stop gained 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 (★★). Synonymous variant affecting the same amino acid position (i.e. C37C) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
NF2
NM_000268.4 stop_gained
NM_000268.4 stop_gained
Scores
4
2
Clinical Significance
Conservation
PhyloP100: 2.38
Publications
0 publications found
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]
NF2 Gene-Disease associations (from GenCC):
- NF2-related schwannomatosisInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P
- familial meningiomaInheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 22-29604109-C-A is Pathogenic according to our data. Variant chr22-29604109-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2737024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000268.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| NF2 | NM_000268.4 | MANE Select | c.111C>A | p.Cys37* | stop_gained | Exon 1 of 16 | NP_000259.1 | ||
| NF2 | NM_001407066.1 | c.111C>A | p.Cys37* | stop_gained | Exon 1 of 17 | NP_001393995.1 | |||
| NF2 | NM_016418.5 | c.111C>A | p.Cys37* | stop_gained | Exon 1 of 17 | NP_057502.2 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| NF2 | ENST00000338641.10 | TSL:1 MANE Select | c.111C>A | p.Cys37* | stop_gained | Exon 1 of 16 | ENSP00000344666.5 | ||
| NF2 | ENST00000397789.3 | TSL:1 | c.111C>A | p.Cys37* | stop_gained | Exon 1 of 17 | ENSP00000380891.3 | ||
| NF2 | ENST00000403999.7 | TSL:1 | c.111C>A | p.Cys37* | stop_gained | Exon 1 of 16 | ENSP00000384797.3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.91e-7 AC: 1AN: 1447886Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1AN XY: 718914 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
1
AN:
1447886
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
718914
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
33278
American (AMR)
AF:
AC:
0
AN:
42556
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25736
East Asian (EAS)
AF:
AC:
0
AN:
39314
South Asian (SAS)
AF:
AC:
0
AN:
84188
European-Finnish (FIN)
AF:
AC:
0
AN:
51884
Middle Eastern (MID)
AF:
AC:
0
AN:
5756
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1105274
Other (OTH)
AF:
AC:
0
AN:
59900
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.275
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
ClinVar submissions as Germline
Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
1
-
-
Neurofibromatosis, type 2 (1)
1
-
-
not provided (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
PhyloP100
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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