22-29674891-C-T

Position:

• chr22-29674891-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000268.4(NF2):​c.1396C>T​(p.Arg466Ter) variant causes a stop gained 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R466R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NF2 NM_000268.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 4.87

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-29674891-C-T is Pathogenic according to our data. Variant chr22-29674891-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-29674891-C-T is described in Lovd as [Pathogenic]. Variant chr22-29674891-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF2	NM_000268.4	c.1396C>T	p.Arg466Ter	stop_gained	13/16	ENST00000338641.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF2	ENST00000338641.10	c.1396C>T	p.Arg466Ter	stop_gained	13/16	1	NM_000268.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1422466 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 703622

Gnomad4 AFR exome AF: 0.00

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: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 2 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Feb 21, 2022	ClinVar contains an entry for this variant (Variation ID: 3295). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 2 (PMID: 7913580, 8012353, 12566519, 18033041, 18766994, 24815379, 26066488). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg466*) in the NF2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NF2 are known to be pathogenic (PMID: 9643284, 16983642). -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1994	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Sep 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 08, 2019	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data. Damaging to protein function(s) relevant to disease mechanism. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 23, 2017

The p.R466* pathogenic mutation (also known as c.1396C>T), located in coding exon 13 of the NF2 gene, results from a C to T substitution at nucleotide position 1396. This changes the amino acid from an arginine to a stop codon within coding exon 13. This mutation has been reported in multiple individuals with clinical features of neurofibromatosis type 2 (MacCollin M et al. Am. J. Hum. Genet. 1994 Aug;55(2):314-20; Bourn D et al. Hum. Genet. 1995 May;95(5):572-4; Parry DM et al. Am. J. Hum. Genet. 1996 Sep;59(3):529-39; Kluwe L et al. J. Med. Genet. 2003 Feb;40(2):109-14; Grant EA et al. Ophthalmic Genet. 2008 Sep;29(3):133-8; Goutagny S et al. J. Neurooncol. 2015 Apr;122(2):313-20). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A
Vest4		0.97
ClinPred		1.0	D
GERP RS		4.5

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: rs74315504; hg19: chr22-30070880; COSMIC: COSV58519978;