chr22-29604000-T-C

Position:

• chr22-29604000-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000268.4(NF2):​c.2T>C​(p.Met1?) variant causes a start lost change. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NF2 NM_000268.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.34

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF2	NM_000268.4	c.2T>C	p.Met1?	start_lost	1/16	ENST00000338641.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF2	ENST00000338641.10	c.2T>C	p.Met1?	start_lost	1/16	1	NM_000268.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 08, 2023

Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease, however a downstream in-frame Methionine residue is present which, if utilized, may result in a functional protein; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 35332608) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	26
DANN	Benign	0.97
DEOGEN2	Benign	0.34	.;T;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;D;D;D;.;.;D;.;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.70	D
MutationTaster	Benign	0.95	D;D;D;D;D;D;D;D;N;N;N
PROVEAN	Benign	-0.56	N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D
Polyphen		0.87	P;D;.;D;D;P;P;D;D;D
Vest4		0.87
MutPred		0.94		Gain of phosphorylation at M1 (P = 0.06);Gain of phosphorylation at M1 (P = 0.06);Gain of phosphorylation at M1 (P = 0.06);Gain of phosphorylation at M1 (P = 0.06);Gain of phosphorylation at M1 (P = 0.06);Gain of phosphorylation at M1 (P = 0.06);Gain of phosphorylation at M1 (P = 0.06);Gain of phosphorylation at M1 (P = 0.06);Gain of phosphorylation at M1 (P = 0.06);Gain of phosphorylation at M1 (P = 0.06);
MVP		0.92
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.80

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555978325; hg19: chr22-29999989;