22-29668394-T-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_000268.4(NF2):c.947T>G(p.Leu316Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,858 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

NF2
NM_000268.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:4

Conservation

PhyloP100: 8.01

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6

Variant 22-29668394-T-G is Benign according to our data. Variant chr22-29668394-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 380975.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=5}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000046 (7/152146) while in subpopulation AMR AF= 0.000196 (3/15276). AF 95% confidence interval is 0.0000529. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF2	NM_000268.4 link	c.947T>G	p.Leu316Trp	missense_variant	Exon 10 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.947T>G	p.Leu316Trp	missense_variant	Exon 10 of 16	1	NM_000268.4	ENSP00000344666.5		P35240-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251484

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1461712

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727156

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000179

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:

0.0000234

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000557

Hom.:

Bravo

AF:

0.0000604

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Neurofibromatosis, type 2

Uncertain:3Benign:1

Jun 11, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with tryptophan at codon 316 of the NF2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has reported that this variant does not impact interaction with HEI10, a cell cycle regulator, in a yeast two-hybrid assay (PMID: 16532029). This variant has been reported in an individual affected with bilateral vestibular schwannomas (PMID: 16983642). This variant has been identified in 8/282878 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. -

Nov 22, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

An NF2 c.947T>G (p.Leu316Trp) variant was identified at a near heterozygous allelic fraction of 49.5%, a frequency which may be consistent with germline origin. This variant has been reported in the literature in a germline state in an individual with bilateral vestibular schwannomas (Ahronowitz I et al., PMID: 16983642) and in two Brazilian individuals with breast cancer (Guindalini RSC et al., PMID: 35264596). It has been reported in the ClinVar database as a germline variant of uncertain significance by four submitters, likely benign by one submitter and benign by one submitter (ClinVar Variation ID: 380975). The NF2 c.947T>G (p.Leu316Trp) variant is observed on 44/1,613,858 alleles in the general population (gnomAD v.4.1.0). Functional studies performed did not indicate a difference in binding with the p.Leu316Trp variant (Grönholm M et al., PMID: 16532029). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to NF2 function. Due to conflicting information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time. -

Nov 07, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1

Jul 12, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate no damaging effect on interaction with HEI10 (PMID: 16532029); This variant is associated with the following publications: (PMID: 16324214, 11756419, 17134719, 22482125, 35264596, 16983642, 16532029, 35332608) -

Neurofibromatosis, type 2;C3551915:Familial meningioma

Uncertain:1

Mar 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Dec 20, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NF2 c.947T>G (p.Leu316Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.7e-05 in 1613858 control chromosomes. The observed variant frequency is approximately 2.7-fold of the estimated maximal expected allele frequency for a pathogenic variant in NF2 causing Neurofibromatosis, type 2 phenotype (1e-05), suggesting the variant may be benign. c.947T>G has been reported in the literature in at least one individual affected with Neurofibromatosis, type 2 and one individual affected with breast cancer, both without evidence of causality (e.g. Ahronowitz_2007, Guindalini_2022). These reports do not provide unequivocal conclusions about association of the variant with Neurofibromatosis, type 2. Two publications report experimental evidence evaluating an impact on protein function, showing the variant does not impair binding with targeted proteins involved in cell-cycle regulation or growth supression, however, additional evidence is needed to determine the role of these interactions in disease (e.g. Gronholm_2006, Roehrig_2021). The following publications have been ascertained in the context of this evaluation (PMID: 16983642, 16532029, 35264596, 34424918). ClinVar contains an entry for this variant (Variation ID: 380975). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary cancer

Benign:1

Sep 11, 2024

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity. -

Hereditary cancer-predisposing syndrome

Benign:1

Aug 06, 2021

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.096

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Benign

0.96

DEOGEN2

Uncertain

0.79

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

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

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

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.63

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

MetaSVM

Uncertain

0.12

MutationAssessor

Benign

1.1

L;L;.;L;.;.;L;.;L

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-4.1

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

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0020

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

Sift4G

Pathogenic

0.0010

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

Polyphen

1.0

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

Vest4

0.51

MutPred

0.82

Loss of ubiquitination at K312 (P = 0.0505);Loss of ubiquitination at K312 (P = 0.0505);.;Loss of ubiquitination at K312 (P = 0.0505);.;.;Loss of ubiquitination at K312 (P = 0.0505);.;Loss of ubiquitination at K312 (P = 0.0505);

MVP

0.93

MPC

2.0

ClinPred

0.80

GERP RS

5.6

Varity_R

0.67

gMVP

0.58

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