22-29603753-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000268.4(NF2):c.-246C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 517,514 control chromosomes in the GnomAD database, including 271 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (58 hom., cov: 33)
  • Exomes 𝑓: 0.015 (213 hom.)
• Consequence: NF2 NM_000268.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0400

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 22-29603753-C-G is Benign according to our data. Variant chr22-29603753-C-G is described in ClinVar as [Benign]. Clinvar id is 341063.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF2	NM_000268.4	c.-246C>G		5_prime_UTR_variant	1/16	ENST00000338641.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF2	ENST00000338641.10	c.-246C>G		5_prime_UTR_variant	1/16	1	NM_000268.4	P1

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1646 AN: 152124 Hom.: 58 Cov.: 33

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0301

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.134

Gnomad SAS AF: 0.0323

Gnomad FIN AF: 0.00423

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00243

Gnomad OTH AF: 0.0139

GnomAD4 exome AF: 0.0147 AC: 5352 AN: 365274 Hom.: 213 Cov.: 0 AF XY: 0.0147 AC XY: 2799 AN XY: 190316

Gnomad4 AFR exome AF: 0.00189

Gnomad4 AMR exome AF: 0.0542

Gnomad4 ASJ exome AF: 0.0104

Gnomad4 EAS exome AF: 0.113

Gnomad4 SAS exome AF: 0.0216

Gnomad4 FIN exome AF: 0.00432

Gnomad4 NFE exome AF: 0.00272

Gnomad4 OTH exome AF: 0.0137

GnomAD4 genome AF: 0.0108 AC: 1649 AN: 152240 Hom.: 58 Cov.: 33 AF XY: 0.0120 AC XY: 890 AN XY: 74434

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.0302

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.135

Gnomad4 SAS AF: 0.0325

Gnomad4 FIN AF: 0.00423

Gnomad4 NFE AF: 0.00243

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.00635 Hom.: 5

Bravo AF: 0.0152

Asia WGS AF: 0.0560 AC: 195 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurofibromatosis, type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	6.8
Dann	Benign	0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs56733822; hg19: chr22-29999742;