NM_000268.4:c.364-39A>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000268.4(NF2):c.364-39A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 1,528,952 control chromosomes in the GnomAD database, including 28,938 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 2387 hom., cov: 32)

Exomes 𝑓: 0.18 ( 26551 hom. )

Consequence

NF2
NM_000268.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.64

Publications

20 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 22-29642163-A-C is Benign according to our data. Variant chr22-29642163-A-C is described in ClinVar as Benign. ClinVar VariationId is 262993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.55 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF2	NM_000268.4 link	c.364-39A>C		intron_variant	Intron 3 of 15	ENST00000338641.10	NP_000259.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF2	ENST00000338641.10 link	c.364-39A>C		intron_variant	Intron 3 of 15	1	NM_000268.4	ENSP00000344666.5

Frequencies

GnomAD3 genomes

AF:

0.149

AC:

22627

AN:

152034

Hom.:

2393

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0418

Gnomad AMI

AF:

0.134

Gnomad AMR

AF:

0.182

Gnomad ASJ

AF:

0.233

Gnomad EAS

AF:

0.567

Gnomad SAS

AF:

0.139

Gnomad FIN

AF:

0.137

Gnomad MID

AF:

0.194

Gnomad NFE

AF:

0.172

Gnomad OTH

AF:

0.170

GnomAD2 exomes

AF:

0.194

AC:

48368

AN:

249720

AF XY:

0.190

show subpopulations

Gnomad AFR exome

AF:

0.0393

Gnomad AMR exome

AF:

0.207

Gnomad ASJ exome

AF:

0.227

Gnomad EAS exome

AF:

0.586

Gnomad FIN exome

AF:

0.143

Gnomad NFE exome

AF:

0.173

Gnomad OTH exome

AF:

0.187

GnomAD4 exome

AF:

0.181

AC:

249605

AN:

1376798

Hom.:

26551

Cov.:

AF XY:

0.179

AC XY:

123719

AN XY:

689934

show subpopulations

African (AFR)

AF:

0.0367

AC:

1164

AN:

31756

American (AMR)

AF:

0.203

AC:

9017

AN:

44506

Ashkenazi Jewish (ASJ)

AF:

0.224

AC:

5730

AN:

25572

East Asian (EAS)

AF:

0.553

AC:

21700

AN:

39222

South Asian (SAS)

AF:

0.126

AC:

10661

AN:

84476

European-Finnish (FIN)

AF:

0.143

AC:

7634

AN:

53370

Middle Eastern (MID)

AF:

0.189

AC:

1056

AN:

5588

European-Non Finnish (NFE)

AF:

0.176

AC:

181864

AN:

1034810

Other (OTH)

AF:

0.187

AC:

10779

AN:

57498

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

10831

21662

32492

43323

54154

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6402

12804

19206

25608

32010

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.149

AC:

22615

AN:

152154

Hom.:

2387

Cov.:

AF XY:

0.149

AC XY:

11097

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.0418

AC:

1735

AN:

41520

American (AMR)

AF:

0.182

AC:

2780

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.233

AC:

808

AN:

3468

East Asian (EAS)

AF:

0.567

AC:

2934

AN:

5172

South Asian (SAS)

AF:

0.139

AC:

671

AN:

4822

European-Finnish (FIN)

AF:

0.137

AC:

1447

AN:

10574

Middle Eastern (MID)

AF:

0.182

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.172

AC:

11711

AN:

67984

Other (OTH)

AF:

0.167

AC:

354

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

940

1880

2819

3759

4699

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

254

508

762

1016

1270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.170

Hom.:

1975

Bravo

AF:

0.154

Asia WGS

AF:

0.287

AC:

997

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 22, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Neurofibromatosis, type 2

Benign:2

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.036

(source)

DANN

Benign

0.49

PhyloP100

-1.6

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over