Genetic Variant NF2:p.Ala340Thr (chr22-29671844-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4BP6BS1BS2

The NM_000268.4(NF2):c.1018G>A(p.Ala340Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,613,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A340S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

NF2
NM_000268.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 7.73

Publications

5 publications found

Variant links:

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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
familial meningioma
Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

NF2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.26989993).

BP6

Variant 22-29671844-G-A is Benign according to our data. Variant chr22-29671844-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 527708.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000356 (52/1461752) while in subpopulation SAS AF = 0.0000812 (7/86252). AF 95% confidence interval is 0.0000376. There are 0 homozygotes in GnomAdExome4. There are 22 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 52 AD,Unknown gene.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NF2	NM_000268.4	MANE Select	c.1018G>A	p.Ala340Thr	missense	Exon 11 of 16	NP_000259.1	P35240-1
NF2	NM_001407066.1		c.1018G>A	p.Ala340Thr	missense	Exon 11 of 17	NP_001393995.1	P35240-3
NF2	NM_016418.5		c.1018G>A	p.Ala340Thr	missense	Exon 11 of 17	NP_057502.2	P35240-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NF2	ENST00000338641.10	TSL:1 MANE Select	c.1018G>A	p.Ala340Thr	missense	Exon 11 of 16	ENSP00000344666.5	P35240-1
NF2	ENST00000397789.3	TSL:1	c.1018G>A	p.Ala340Thr	missense	Exon 11 of 17	ENSP00000380891.3	P35240-3
NF2	ENST00000403999.7	TSL:1	c.1018G>A	p.Ala340Thr	missense	Exon 11 of 16	ENSP00000384797.3	P35240-3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251410

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000356

AC:

AN:

1461752

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727178

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000360

AC:

AN:

1111942

Other (OTH)

AF:

0.0000497

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41418

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000676

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neurofibromatosis, type 2 (3)

Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.058

MetaRNN

Benign

0.27

MetaSVM

Benign

-0.32

MutationAssessor

Benign

1.4

PhyloP100

7.7

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.34

Sift

Benign

0.35

Sift4G

Benign

0.52

Polyphen

0.019

Vest4

0.47

MutPred

0.29

Gain of phosphorylation at A340 (P = 0.0031)

MVP

0.74

MPC

0.64

ClinPred

0.32

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.18

Mutation Taster

=57/43

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over