dbSNP rs1556001358: NF2:p.Gln453Lys (chr22-29674852-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000268.4(NF2):c.1357C>A(p.Gln453Lys) 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 benign 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. Q453E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NF2
NM_000268.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.90

Publications

1 publications found

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]

NF2 Gene-Disease associations (from GenCC):

NF2-related schwannomatosis
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P
familial meningioma
Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

NF2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22785488).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NF2	NM_000268.4	MANE Select	c.1357C>A	p.Gln453Lys	missense	Exon 13 of 16	NP_000259.1
NF2	NM_001407066.1		c.1357C>A	p.Gln453Lys	missense	Exon 13 of 17	NP_001393995.1
NF2	NM_016418.5		c.1357C>A	p.Gln453Lys	missense	Exon 13 of 17	NP_057502.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NF2	ENST00000338641.10	TSL:1 MANE Select	c.1357C>A	p.Gln453Lys	missense	Exon 13 of 16	ENSP00000344666.5
NF2	ENST00000397789.3	TSL:1	c.1357C>A	p.Gln453Lys	missense	Exon 13 of 17	ENSP00000380891.3
NF2	ENST00000403999.7	TSL:1	c.1357C>A	p.Gln453Lys	missense	Exon 13 of 16	ENSP00000384797.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1407850

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

695126

African (AFR)

AF:

0.00

AC:

AN:

32138

American (AMR)

AF:

0.00

AC:

AN:

36864

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25218

East Asian (EAS)

AF:

0.00

AC:

AN:

36832

South Asian (SAS)

AF:

0.00

AC:

AN:

79674

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49862

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1083222

Other (OTH)

AF:

0.00

AC:

AN:

58340

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.099

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.23

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.2

PhyloP100

7.9

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.33

REVEL

Uncertain

0.32

Sift

Benign

0.88

Sift4G

Benign

0.66

Polyphen

0.0050

Vest4

0.48

MutPred

0.59

Gain of ubiquitination at Q453 (P = 0.0177)

MVP

0.77

MPC

1.2

ClinPred

0.93

GERP RS

5.6

Varity_R

0.13

gMVP

0.69

Mutation Taster

=25/175

disease causing (fs/PTC)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over