NM_000268.4:c.851A>T

Variant names:

• chr22-29665030-A-T
• rs764034925
• NM_000268.4:c.851A>T

Variant summary

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

The NM_000268.4(NF2):​c.851A>T​(p.Lys284Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K284R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NF2 NM_000268.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.04
• 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 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF2	NM_000268.4	MANE Select	c.851A>T	p.Lys284Met	missense	Exon 9 of 16	NP_000259.1
	NF2	NM_001407066.1		c.851A>T	p.Lys284Met	missense	Exon 9 of 17	NP_001393995.1
	NF2	NM_016418.5		c.851A>T	p.Lys284Met	missense	Exon 9 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.851A>T	p.Lys284Met	missense	Exon 9 of 16	ENSP00000344666.5
	NF2	ENST00000397789.3	TSL:1	c.851A>T	p.Lys284Met	missense	Exon 9 of 17	ENSP00000380891.3
	NF2	ENST00000403999.7	TSL:1	c.851A>T	p.Lys284Met	missense	Exon 9 of 16	ENSP00000384797.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251186 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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.29	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	1.8	L
PhyloP100		9.0
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.70	N
REVEL	Uncertain	0.54
Sift	Benign	0.054	T
Sift4G	Benign	0.085	T
Polyphen		0.059	B
Vest4		0.78
MutPred		0.48		Loss of catalytic residue at K284 (P = 0.009)
MVP		0.88
MPC		1.9
ClinPred		0.74	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.64
gMVP		0.63
Mutation Taster		=30/70	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: rs764034925; hg19: chr22-30061019;