22-29695156-T-C

Variant names:

• chr22-29695156-T-C
• rs1008515
• NM_000268.4:c.*354T>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.*354T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 457,612 control chromosomes in the GnomAD database, including 15,200 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4495 hom., cov: 33)
  • Exomes 𝑓: 0.25 (10705 hom.)
• Consequence: NF2 NM_000268.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.12
• Publications: 14 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=-0.91).
• BP6: Variant 22-29695156-T-C is Benign according to our data. Variant chr22-29695156-T-C is described in ClinVar as Benign. ClinVar VariationId is 341085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.424 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF2	NM_000268.4	MANE Select	c.*354T>C		3_prime_UTR	Exon 16 of 16	NP_000259.1
	NF2	NR_176267.1		n.1527T>C		non_coding_transcript_exon	Exon 8 of 8
	NF2	NM_016418.5		c.*414T>C		3_prime_UTR	Exon 17 of 17	NP_057502.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF2	ENST00000338641.10	TSL:1 MANE Select	c.*354T>C		3_prime_UTR	Exon 16 of 16	ENSP00000344666.5
	NF2	ENST00000361452.8	TSL:1	c.*414T>C		3_prime_UTR	Exon 16 of 16	ENSP00000354897.4
	NF2	ENST00000413209.6	TSL:1	c.*354T>C		3_prime_UTR	Exon 5 of 5	ENSP00000409921.2

Frequencies

GnomAD3 genomes AF: 0.236 AC: 35939 AN: 152008 Hom.: 4495 Cov.: 33

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.439

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.238

Gnomad OTH AF: 0.220

GnomAD4 exome AF: 0.254 AC: 77442 AN: 305486 Hom.: 10705 Cov.: 0 AF XY: 0.254 AC XY: 40310 AN XY: 158748

African (AFR) AF: 0.215 AC: 2167 AN: 10078

American (AMR) AF: 0.224 AC: 3233 AN: 14444

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 1715 AN: 10418

East Asian (EAS) AF: 0.456 AC: 9686 AN: 21220

South Asian (SAS) AF: 0.257 AC: 10239 AN: 39896

European-Finnish (FIN) AF: 0.294 AC: 3398 AN: 11566

Middle Eastern (MID) AF: 0.210 AC: 277 AN: 1318

European-Non Finnish (NFE) AF: 0.238 AC: 42433 AN: 178410

Other (OTH) AF: 0.237 AC: 4294 AN: 18136

GnomAD4 genome AF: 0.236 AC: 35961 AN: 152126 Hom.: 4495 Cov.: 33 AF XY: 0.240 AC XY: 17844 AN XY: 74356

African (AFR) AF: 0.216 AC: 8974 AN: 41532

American (AMR) AF: 0.192 AC: 2929 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 590 AN: 3472

East Asian (EAS) AF: 0.439 AC: 2268 AN: 5166

South Asian (SAS) AF: 0.260 AC: 1254 AN: 4818

European-Finnish (FIN) AF: 0.292 AC: 3085 AN: 10580

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.238 AC: 16153 AN: 67972

Other (OTH) AF: 0.218 AC: 460 AN: 2110

Alfa AF: 0.227 Hom.: 4947

Bravo AF: 0.232

Asia WGS AF: 0.320 AC: 1111 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.45
DANN	Benign	0.34
PhyloP100		-2.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1008515; hg19: chr22-30091145;