22-29642163-A-C

Variant names:

• chr22-29642163-A-C
• rs2530664
• NM_000268.4:c.364-39A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000268.4(NF2):​c.364-39A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 1,528,952 control chromosomes in the GnomAD database, including 28,938 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2387 hom., cov: 32)
  • Exomes 𝑓: 0.18 (26551 hom.)
• Consequence: NF2 NM_000268.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.64
• Publications: 20 publications found

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 Gene-Disease associations (from GenCC):

• NF2-related schwannomatosis

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• familial meningioma

  Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 22-29642163-A-C is Benign according to our data. Variant chr22-29642163-A-C is described in ClinVar as Benign. ClinVar VariationId is 262993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.55 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000268.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF2	NM_000268.4	MANE Select	c.364-39A>C		intron	N/A	NP_000259.1
	NF2	NM_001407066.1		c.364-39A>C		intron	N/A	NP_001393995.1
	NF2	NM_016418.5		c.364-39A>C		intron	N/A	NP_057502.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF2	ENST00000338641.10	TSL:1 MANE Select	c.364-39A>C		intron	N/A	ENSP00000344666.5
	NF2	ENST00000397789.3	TSL:1	c.364-39A>C		intron	N/A	ENSP00000380891.3
	NF2	ENST00000403999.7	TSL:1	c.364-39A>C		intron	N/A	ENSP00000384797.3

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22627 AN: 152034 Hom.: 2393 Cov.: 32

Gnomad AFR AF: 0.0418

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.182

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.567

Gnomad SAS AF: 0.139

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.194

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.170

GnomAD2 exomes AF: 0.194 AC: 48368 AN: 249720 AF XY: 0.190

Gnomad AFR exome AF: 0.0393

Gnomad AMR exome AF: 0.207

Gnomad ASJ exome AF: 0.227

Gnomad EAS exome AF: 0.586

Gnomad FIN exome AF: 0.143

Gnomad NFE exome AF: 0.173

Gnomad OTH exome AF: 0.187

GnomAD4 exome AF: 0.181 AC: 249605 AN: 1376798 Hom.: 26551 Cov.: 21 AF XY: 0.179 AC XY: 123719 AN XY: 689934

African (AFR) AF: 0.0367 AC: 1164 AN: 31756

American (AMR) AF: 0.203 AC: 9017 AN: 44506

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 5730 AN: 25572

East Asian (EAS) AF: 0.553 AC: 21700 AN: 39222

South Asian (SAS) AF: 0.126 AC: 10661 AN: 84476

European-Finnish (FIN) AF: 0.143 AC: 7634 AN: 53370

Middle Eastern (MID) AF: 0.189 AC: 1056 AN: 5588

European-Non Finnish (NFE) AF: 0.176 AC: 181864 AN: 1034810

Other (OTH) AF: 0.187 AC: 10779 AN: 57498

GnomAD4 genome AF: 0.149 AC: 22615 AN: 152154 Hom.: 2387 Cov.: 32 AF XY: 0.149 AC XY: 11097 AN XY: 74384

African (AFR) AF: 0.0418 AC: 1735 AN: 41520

American (AMR) AF: 0.182 AC: 2780 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 808 AN: 3468

East Asian (EAS) AF: 0.567 AC: 2934 AN: 5172

South Asian (SAS) AF: 0.139 AC: 671 AN: 4822

European-Finnish (FIN) AF: 0.137 AC: 1447 AN: 10574

Middle Eastern (MID) AF: 0.182 AC: 53 AN: 292

European-Non Finnish (NFE) AF: 0.172 AC: 11711 AN: 67984

Other (OTH) AF: 0.167 AC: 354 AN: 2114

Alfa AF: 0.170 Hom.: 1975

Bravo AF: 0.154

Asia WGS AF: 0.287 AC: 997 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Neurofibromatosis, type 2 (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.036
DANN	Benign	0.49
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2530664; hg19: chr22-30038152; COSMIC: COSV58520480;