dbSNP rs75296199: NF2:c.*644A>G (chr22-29683699-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 8P and 10B. PVS1BP6_ModerateBS1BS2

The NM_001407066.1(NF2):c.*10-2A>G variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000763 in 1,073,498 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00054 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00080 ( 1 hom. )

Consequence

NF2
NM_001407066.1 splice_acceptor, intron

Scores

Splicing: ADA: 0.00001103

Clinical Significance

Likely benign criteria provided, single submitter U:2B:1O:1

Conservation

PhyloP100: -3.31

Publications

2 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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, 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: Likely_benign. The variant received -2 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 12, offset of 14, new splice context is: cttcggcttcctctccatAGgct. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

BP6

Variant 22-29683699-A-G is Benign according to our data. Variant chr22-29683699-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 135570.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000538 (82/152308) while in subpopulation AMR AF = 0.00118 (18/15300). AF 95% confidence interval is 0.00076. There are 0 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 82 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407066.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NF2	NM_000268.4	MANE Select	c.1737+2098A>G	intron	N/A	NP_000259.1	P35240-1
NF2	NM_181825.3		c.*644A>G	3_prime_UTR	Exon 16 of 16	NP_861546.1	P35240-3
NF2	NM_001407066.1		c.*10-2A>G	splice_acceptor intron	N/A	NP_001393995.1	P35240-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NF2	ENST00000403999.7	TSL:1	c.*644A>G	3_prime_UTR	Exon 16 of 16	ENSP00000384797.3	P35240-3
NF2	ENST00000338641.10	TSL:1 MANE Select	c.1737+2098A>G	intron	N/A	ENSP00000344666.5	P35240-1
NF2	ENST00000397789.3	TSL:1	c.*24+620A>G	intron	N/A	ENSP00000380891.3	P35240-3

Frequencies

GnomAD3 genomes

AF:

0.000539

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000808

Gnomad OTH

AF:

0.000478

GnomAD4 exome

AF:

0.000800

AC:

737

AN:

921190

Hom.:

Cov.:

AF XY:

0.000773

AC XY:

329

AN XY:

425864

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

19594

American (AMR)

AF:

0.00105

AC:

AN:

5730

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10192

East Asian (EAS)

AF:

0.00

AC:

AN:

15240

South Asian (SAS)

AF:

0.000440

AC:

AN:

18196

European-Finnish (FIN)

AF:

0.00

AC:

AN:

424

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2100

European-Non Finnish (NFE)

AF:

0.000849

AC:

692

AN:

815466

Other (OTH)

AF:

0.000905

AC:

AN:

34248

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

121

161

201

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<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:

0.000538

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.000537

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41576

American (AMR)

AF:

0.00118

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000808

AC:

AN:

68028

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000570

Hom.:

Bravo

AF:

0.000763

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neurofibromatosis, type 2 (1)

NF2-related disorder (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

0.032

(source)

DANN

Benign

0.30

PhyloP100

-3.3

Mutation Taster

=78/22

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000011

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.060

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over