rs1318882444

Variant names:

• chr22-29674859-A-C
• NM_000268.4:c.1364A>C

Your query was ambiguous. Multiple possible variants found:

• chr22-29674859-A-C
• chr22-29674859-A-G
• chr22-29674859-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000268.4(NF2):​c.1364A>C​(p.Lys455Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000709 in 1,411,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: NF2 NM_000268.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.32

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF2	NM_000268.4	c.1364A>C	p.Lys455Thr	missense_variant	Exon 13 of 16	ENST00000338641.10	NP_000259.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF2	ENST00000338641.10	c.1364A>C	p.Lys455Thr	missense_variant	Exon 13 of 16	1	NM_000268.4	ENSP00000344666.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.09e-7 AC: 1 AN: 1411378 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 697176

Gnomad4 AFR exome AF: 0.0000310

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 2 Uncertain:1

Dec 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 455 of the NF2 protein (p.Lys455Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NF2-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NF2 protein function. -

Hereditary cancer-predisposing syndrome Uncertain:1

Jul 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.K455T variant (also known as c.1364A>C), located in coding exon 13 of the NF2 gene, results from an A to C substitution at nucleotide position 1364. The lysine at codon 455 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D;.;.;.;.;.;.;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D;D;.;.;D;.;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.9	M;.;.;M;.;.;M;.;M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.6	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.062	T;D;D;T;D;D;T;T;T
Polyphen		1.0	D;D;D;P;D;D;P;D;P
Vest4		0.65
MutPred		0.62		Loss of ubiquitination at K455 (P = 0.0063);.;.;Loss of ubiquitination at K455 (P = 0.0063);.;.;Loss of ubiquitination at K455 (P = 0.0063);.;Loss of ubiquitination at K455 (P = 0.0063);
MVP		0.83
MPC		1.7
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.66
gMVP		0.78

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-30070848;