22-29655652-A-G

Variant names:

• chr22-29655652-A-G
• rs1555993319
• NM_000268.4:c.575A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000268.4(NF2):​c.575A>G​(p.Tyr192Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as other (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y192N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF2 NM_000268.4 missense
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: 9.19
• Publications: 1 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000268.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF2	NM_000268.4	MANE Select	c.575A>G	p.Tyr192Cys	missense	Exon 6 of 16	NP_000259.1
	NF2	NM_001407066.1		c.575A>G	p.Tyr192Cys	missense	Exon 6 of 17	NP_001393995.1
	NF2	NM_016418.5		c.575A>G	p.Tyr192Cys	missense	Exon 6 of 17	NP_057502.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF2	ENST00000338641.10	TSL:1 MANE Select	c.575A>G	p.Tyr192Cys	missense	Exon 6 of 16	ENSP00000344666.5
	NF2	ENST00000397789.3	TSL:1	c.575A>G	p.Tyr192Cys	missense	Exon 6 of 17	ENSP00000380891.3
	NF2	ENST00000403999.7	TSL:1	c.575A>G	p.Tyr192Cys	missense	Exon 6 of 16	ENSP00000384797.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Choroid plexus carcinoma Other:1

May 01, 2016

Donald Williams Parsons Laboratory, Baylor College of Medicine

Significance: other

Review Status: no assertion criteria provided

Collection Method: clinical testing

3: Mutations in other consensus cancer genes, not currently considered targetable

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		9.2
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-8.4	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.78		Loss of disorder (P = 0.1244)
MVP		0.94
MPC		1.9
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.97
gMVP		0.88
Mutation Taster		=20/80	disease causing

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

Other links and lift over

dbSNP: rs1555993319; hg19: chr22-30051641;