chr22-29603795-C-A

Position:

• chr22-29603795-C-A

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.-204C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 571,324 control chromosomes in the GnomAD database, including 37,610 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9149 hom., cov: 34)
  • Exomes 𝑓: 0.36 (28461 hom.)
• Consequence: NF2 NM_000268.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.171

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]

NF2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 22-29603795-C-A is Benign according to our data. Variant chr22-29603795-C-A is described in ClinVar as [Benign]. Clinvar id is 341065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.481 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF2	NM_000268.4	c.-204C>A		5_prime_UTR_variant	1/16	ENST00000338641.10	NP_000259.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF2	ENST00000338641	c.-204C>A		5_prime_UTR_variant	1/16	1	NM_000268.4	ENSP00000344666.5

Frequencies

GnomAD3 genomes AF: 0.345 AC: 52435 AN: 151892 Hom.: 9138 Cov.: 34

Gnomad AFR AF: 0.306

Gnomad AMI AF: 0.375

Gnomad AMR AF: 0.444

Gnomad ASJ AF: 0.347

Gnomad EAS AF: 0.193

Gnomad SAS AF: 0.496

Gnomad FIN AF: 0.391

Gnomad MID AF: 0.404

Gnomad NFE AF: 0.339

Gnomad OTH AF: 0.356

GnomAD4 exome AF: 0.359 AC: 150629 AN: 419316 Hom.: 28461 Cov.: 3 AF XY: 0.368 AC XY: 81108 AN XY: 220454

Gnomad4 AFR exome AF: 0.311

Gnomad4 AMR exome AF: 0.466

Gnomad4 ASJ exome AF: 0.366

Gnomad4 EAS exome AF: 0.196

Gnomad4 SAS exome AF: 0.514

Gnomad4 FIN exome AF: 0.390

Gnomad4 NFE exome AF: 0.343

Gnomad4 OTH exome AF: 0.362

GnomAD4 genome AF: 0.345 AC: 52458 AN: 152008 Hom.: 9149 Cov.: 34 AF XY: 0.352 AC XY: 26175 AN XY: 74306

Gnomad4 AFR AF: 0.306

Gnomad4 AMR AF: 0.445

Gnomad4 ASJ AF: 0.347

Gnomad4 EAS AF: 0.193

Gnomad4 SAS AF: 0.498

Gnomad4 FIN AF: 0.391

Gnomad4 NFE AF: 0.339

Gnomad4 OTH AF: 0.352

Alfa AF: 0.336 Hom.: 1063

Bravo AF: 0.343

Asia WGS AF: 0.353 AC: 1227 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Neurofibromatosis, type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	-0.73
CADD	Benign	9.2
DANN	Benign	0.71
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: rs1800539; hg19: chr22-29999784;