22-29603889-G-C

Variant names:

• chr22-29603889-G-C
• rs1800540
• NM_000268.4:c.-110G>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000268.4(NF2):​c.-110G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.875 in 826,994 control chromosomes in the GnomAD database, including 317,277 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (57656 hom., cov: 35)
  • Exomes 𝑓: 0.88 (259621 hom.)
• Consequence: NF2 NM_000268.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.279

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 22-29603889-G-C is Benign according to our data. Variant chr22-29603889-G-C is described in ClinVar as [Benign]. Clinvar id is 341066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.925 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF2	NM_000268.4	c.-110G>C		5_prime_UTR_variant	Exon 1 of 16	ENST00000338641.10	NP_000259.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF2	ENST00000338641	c.-110G>C		5_prime_UTR_variant	Exon 1 of 16	1	NM_000268.4	ENSP00000344666.5

Frequencies

GnomAD3 genomes AF: 0.870 AC: 132246 AN: 152018 Hom.: 57606 Cov.: 35

Gnomad AFR AF: 0.849

Gnomad AMI AF: 0.851

Gnomad AMR AF: 0.898

Gnomad ASJ AF: 0.903

Gnomad EAS AF: 0.946

Gnomad SAS AF: 0.845

Gnomad FIN AF: 0.856

Gnomad MID AF: 0.904

Gnomad NFE AF: 0.872

Gnomad OTH AF: 0.892

GnomAD4 exome AF: 0.877 AC: 591539 AN: 674858 Hom.: 259621 Cov.: 9 AF XY: 0.875 AC XY: 304382 AN XY: 347734

Gnomad4 AFR exome AF: 0.850

Gnomad4 AMR exome AF: 0.882

Gnomad4 ASJ exome AF: 0.904

Gnomad4 EAS exome AF: 0.963

Gnomad4 SAS exome AF: 0.841

Gnomad4 FIN exome AF: 0.856

Gnomad4 NFE exome AF: 0.876

Gnomad4 OTH exome AF: 0.877

GnomAD4 genome AF: 0.870 AC: 132354 AN: 152136 Hom.: 57656 Cov.: 35 AF XY: 0.869 AC XY: 64621 AN XY: 74376

Gnomad4 AFR AF: 0.849

Gnomad4 AMR AF: 0.898

Gnomad4 ASJ AF: 0.903

Gnomad4 EAS AF: 0.947

Gnomad4 SAS AF: 0.846

Gnomad4 FIN AF: 0.856

Gnomad4 NFE AF: 0.872

Gnomad4 OTH AF: 0.893

Alfa AF: 0.867 Hom.: 7099

Bravo AF: 0.872

Asia WGS AF: 0.890 AC: 3093 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neurofibromatosis, type 2 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.68
CADD	Benign	13
DANN	Benign	0.89

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: rs1800540; hg19: chr22-29999878;