22-29681542-A-T

Variant names:

• chr22-29681542-A-T
• rs557347747
• NM_000268.4:c.1678A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000268.4(NF2):​c.1678A>T​(p.Ile560Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I560V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NF2 NM_000268.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.16
• Publications: 2 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, G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
• familial meningioma

  Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• 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.1678A>T	p.Ile560Phe	missense	Exon 15 of 16	NP_000259.1	P35240-1
	NF2	NM_001407066.1		c.1678A>T	p.Ile560Phe	missense	Exon 15 of 17	NP_001393995.1	P35240-3
	NF2	NM_016418.5		c.1678A>T	p.Ile560Phe	missense	Exon 15 of 17	NP_057502.2	P35240-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF2	ENST00000338641.10	TSL:1 MANE Select	c.1678A>T	p.Ile560Phe	missense	Exon 15 of 16	ENSP00000344666.5	P35240-1
	NF2	ENST00000397789.3	TSL:1	c.1678A>T	p.Ile560Phe	missense	Exon 15 of 17	ENSP00000380891.3	P35240-3
	NF2	ENST00000403999.7	TSL:1	c.1678A>T	p.Ile560Phe	missense	Exon 15 of 16	ENSP00000384797.3	P35240-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251382 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	Neurofibromatosis, type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.071	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.2
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.70	N
REVEL	Uncertain	0.41
Sift	Benign	0.39	T
Sift4G	Benign	0.13	T
Polyphen		0.0	B
Vest4		0.53
MutPred		0.67		Gain of phosphorylation at T556 (P = 0.1716)
MVP		0.90
MPC		1.0
ClinPred		0.18	T
GERP RS		3.9
Varity_R		0.060
gMVP		0.27
Mutation Taster		=45/55	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: rs557347747; hg19: chr22-30077531;