rs200169230
Positions:
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_015080.4(NRXN2):c.1522C>T(p.Arg508Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000483 in 1,613,938 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R508H) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000049 ( 0 hom. )
Consequence
NRXN2
NM_015080.4 missense
NM_015080.4 missense
Scores
3
12
3
Clinical Significance
Conservation
PhyloP100: 4.53
Genes affected
NRXN2 (HGNC:8009): (neurexin 2) This gene encodes a member of the neurexin gene family. The products of these genes function as cell adhesion molecules and receptors in the vertebrate nervous system. These genes utilize two promoters. The majority of transcripts are produced from the upstream promoter and encode alpha-neurexin isoforms while a smaller number of transcripts are produced from the downstream promoter and encode beta-neuresin isoforms. The alpha-neurexins contain epidermal growth factor-like (EGF-like) sequences and laminin G domains, and have been shown to interact with neurexophilins. The beta-neurexins lack EGF-like sequences and contain fewer laminin G domains than alpha-neurexins. Alternative splicing and the use of alternative promoters may generate thousands of transcript variants (PMID: 12036300, PMID: 11944992).[provided by RefSeq, Jun 2010]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
BS2
?
High AC in GnomAd4 at 6 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NRXN2 | NM_015080.4 | c.1522C>T | p.Arg508Cys | missense_variant | 9/23 | ENST00000265459.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NRXN2 | ENST00000265459.11 | c.1522C>T | p.Arg508Cys | missense_variant | 9/23 | 5 | NM_015080.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152226Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000637 AC: 16AN: 251006Hom.: 0 AF XY: 0.0000663 AC XY: 9AN XY: 135724
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GnomAD4 exome AF: 0.0000493 AC: 72AN: 1461712Hom.: 0 Cov.: 32 AF XY: 0.0000550 AC XY: 40AN XY: 727144
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GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152226Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74364
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 17, 2022 | The c.1522C>T (p.R508C) alteration is located in exon 9 (coding exon 8) of the NRXN2 gene. This alteration results from a C to T substitution at nucleotide position 1522, causing the arginine (R) at amino acid position 508 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 28, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;.;T;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Uncertain
T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;M;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;.
Polyphen
P;D;P;.;.
Vest4
MutPred
Loss of MoRF binding (P = 0.0096);.;Loss of MoRF binding (P = 0.0096);.;.;
MVP
MPC
0.90
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at