rs1060503671

Variant names:

• chr22-29604118-C-A
• rs1060503671
• NM_000268.4:c.114+6C>A

Your query was ambiguous. Multiple possible variants found:

• chr22-29604118-C-A
• chr22-29604118-C-G
• chr22-29604118-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000268.4(NF2):​c.114+6C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,439,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NF2 NM_000268.4 splice_region, intron
• Scores: Splicing: ADA: 0.03012
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.361
• Publications: 0 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, G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
• familial meningioma

  Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).

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.114+6C>A		splice_region intron	N/A	NP_000259.1	P35240-1
	NF2	NM_001407066.1		c.114+6C>A		splice_region intron	N/A	NP_001393995.1	P35240-3
	NF2	NM_016418.5		c.114+6C>A		splice_region intron	N/A	NP_057502.2	P35240-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF2	ENST00000338641.10	TSL:1 MANE Select	c.114+6C>A		splice_region intron	N/A	ENSP00000344666.5	P35240-1
	NF2	ENST00000397789.3	TSL:1	c.114+6C>A		splice_region intron	N/A	ENSP00000380891.3	P35240-3
	NF2	ENST00000403999.7	TSL:1	c.114+6C>A		splice_region intron	N/A	ENSP00000384797.3	P35240-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1439496 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 714436

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33156

American (AMR) AF: 0.00 AC: 0 AN: 41422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25620

East Asian (EAS) AF: 0.00 AC: 0 AN: 38996

South Asian (SAS) AF: 0.00 AC: 0 AN: 83356

European-Finnish (FIN) AF: 0.0000195 AC: 1 AN: 51324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 9.09e-7 AC: 1 AN: 1100260

Other (OTH) AF: 0.00 AC: 0 AN: 59612

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0448430), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Neurofibromatosis, type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	14
DANN	Benign	0.94
PhyloP100		-0.36
PromoterAI		0.057	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.030
dbscSNV1_RF	Benign	0.11
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: rs1060503671; hg19: chr22-30000107;