Genetic Variant NM_000268.4:c.48G>C (chr22-29604046-G-C) – 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.48G>C(p.Arg16Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,453,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R16R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NF2
NM_000268.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.38

Publications

0 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=0.25182837).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF2	NM_000268.4 link	c.48G>C	p.Arg16Ser	missense_variant	Exon 1 of 16	ENST00000338641.10	NP_000259.1	P35240-1A0A024R1J8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF2	ENST00000338641.10 link	c.48G>C	p.Arg16Ser	missense_variant	Exon 1 of 16	1	NM_000268.4	ENSP00000344666.5		P35240-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000426

AC:

AN:

234846

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000957

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1453966

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722400

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33386

American (AMR)

AF:

0.00

AC:

AN:

43586

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25884

East Asian (EAS)

AF:

0.00

AC:

AN:

39532

South Asian (SAS)

AF:

0.00

AC:

AN:

84756

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52286

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1108612

Other (OTH)

AF:

0.00

AC:

AN:

60158

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.41

.;T;.;.;.;.;.;.;.;.

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.93

D;D;D;D;.;.;D;.;D;D

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.25

T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.26

MutationAssessor

Benign

1.6

L;L;L;L;L;L;L;L;L;L

PhyloP100

1.4

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-2.2

N;N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.59

Sift

Benign

0.21

T;T;T;T;T;D;D;T;D;T

Sift4G

Benign

0.13

T;T;T;T;T;D;D;T;D;T

Polyphen

0.043

B;B;.;B;P;B;B;P;P;P

Vest4

0.41

MutPred

0.41

Loss of MoRF binding (P = 0.0473);Loss of MoRF binding (P = 0.0473);Loss of MoRF binding (P = 0.0473);Loss of MoRF binding (P = 0.0473);Loss of MoRF binding (P = 0.0473);Loss of MoRF binding (P = 0.0473);Loss of MoRF binding (P = 0.0473);Loss of MoRF binding (P = 0.0473);Loss of MoRF binding (P = 0.0473);Loss of MoRF binding (P = 0.0473);

MVP

0.84

MPC

1.1

ClinPred

0.27

GERP RS

3.0

PromoterAI

-0.067

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.64

gMVP

0.67

Mutation Taster

=43/57

disease causing

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over