rs587778554

Positions:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_000268.4(NF2):c.1007G>A(p.Arg336Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,702 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

NF2
NM_000268.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7O:1

Conservation

PhyloP100: 5.02

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 links:

NF2 (HGNC:):

NF2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF2	NM_000268.4 linkuse as main transcript	c.1007G>A	p.Arg336Gln	missense_variant	11/16	ENST00000338641.10	NP_000259.1	P35240-1A0A024R1J8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF2	ENST00000338641.10 linkuse as main transcript	c.1007G>A	p.Arg336Gln	missense_variant	11/16	1	NM_000268.4	ENSP00000344666.5		P35240-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251398

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135880

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 SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461702

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurofibromatosis, type 2

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 22, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 336 of the NF2 protein (p.Arg336Gln). This variant is present in population databases (rs587778554, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with NF2-related conditions. ClinVar contains an entry for this variant (Variation ID: 134895). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NF2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Apr 03, 2023	This missense variant replaces arginine with glutamine at codon 336 of the NF2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with NF2-related disorders in the literature. This variant has been identified in 3/251398 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Mar 12, 2021

- -

Neurofibromatosis, type 2;C3551915:Familial meningioma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 17, 2024

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2023

The p.R336Q variant (also known as c.1007G>A), located in coding exon 11 of the NF2 gene, results from a G to A substitution at nucleotide position 1007. The arginine at codon 336 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Uncertain

0.060

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.73

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

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

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

M_CAP

Benign

0.078

MetaRNN

Uncertain

0.44

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

MetaSVM

Uncertain

0.029

MutationAssessor

Uncertain

2.6

M;.;M;.;.;M;.;M

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.3

D;D;D;D;D;D;D;D

REVEL

Uncertain

0.48

Sift

Uncertain

0.0020

D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.054

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

Polyphen

0.96

D;P;P;P;P;P;P;P

Vest4

0.58

MutPred

0.34

Gain of ubiquitination at K332 (P = 0.1079);.;Gain of ubiquitination at K332 (P = 0.1079);.;.;Gain of ubiquitination at K332 (P = 0.1079);.;Gain of ubiquitination at K332 (P = 0.1079);

MVP

0.83

MPC

0.79

ClinPred

0.92

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.81

gMVP

0.66

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over