rs1556008383

Variant names:

• chr22-29694748-ACAGCTCA-G
• rs1556008383
• ENST00000397789.3:c.*25-4_*28delACAGCTCAinsG

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_000268.4(NF2):​c.1738-4_1741delACAGCTCAinsG​(p.Leu580fs) variant causes a frameshift, splice acceptor, splice region, intron change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF2 NM_000268.4 frameshift, splice_acceptor, splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.73
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, ClinGen, Orphanet
• familial meningioma

  Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

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

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.028 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF2	NM_000268.4	MANE Select	c.1738-4_1741delACAGCTCAinsG	p.Leu580fs	frameshift splice_acceptor splice_region intron	Exon 16 of 16	NP_000259.1	P35240-1
	NF2	NM_016418.5		c.*10-4_*13delACAGCTCAinsG		splice_region	Exon 17 of 17	NP_057502.2	P35240-3
	NF2	NM_181832.3		c.*25-4_*28delACAGCTCAinsG		splice_region	Exon 17 of 17	NP_861970.1	P35240-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF2	ENST00000397789.3	TSL:1	c.*25-4_*28delACAGCTCAinsG		splice_region	Exon 17 of 17	ENSP00000380891.3	P35240-3
	NF2	ENST00000361452.8	TSL:1	c.*10-4_*13delACAGCTCAinsG		splice_region	Exon 16 of 16	ENSP00000354897.4	P35240-5
	NF2	ENST00000361676.8	TSL:1	c.*10-4_*13delACAGCTCAinsG		splice_region	Exon 16 of 16	ENSP00000355183.4	P35240-6

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Neurofibromatosis, type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.7

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1556008383;

hg19: chr22-30090737;