rs138291758
Positions:
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2
The NM_015080.4(NRXN2):c.2281A>T(p.Met761Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000157 in 1,614,136 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00016 ( 0 hom. )
Consequence
NRXN2
NM_015080.4 missense
NM_015080.4 missense
Scores
1
7
10
Clinical Significance
Conservation
PhyloP100: 5.14
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 -5 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.38368544).
BS2
?
High AC in GnomAd4 at 21 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NRXN2 | NM_015080.4 | c.2281A>T | p.Met761Leu | missense_variant | 11/23 | ENST00000265459.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NRXN2 | ENST00000265459.11 | c.2281A>T | p.Met761Leu | missense_variant | 11/23 | 5 | NM_015080.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000138 AC: 21AN: 152128Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000107 AC: 27AN: 251448Hom.: 0 AF XY: 0.000147 AC XY: 20AN XY: 135908
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GnomAD4 exome AF: 0.000159 AC: 232AN: 1461890Hom.: 0 Cov.: 31 AF XY: 0.000179 AC XY: 130AN XY: 727246
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GnomAD4 genome ? AF: 0.000138 AC: 21AN: 152246Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74436
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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 | Feb 01, 2023 | The c.2281A>T (p.M761L) alteration is located in exon 11 (coding exon 10) of the NRXN2 gene. This alteration results from a A to T substitution at nucleotide position 2281, causing the methionine (M) at amino acid position 761 to be replaced by a leucine (L). 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 | Oct 20, 2014 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;L;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N
REVEL
Pathogenic
Sift
Benign
T;T;T;T
Sift4G
Benign
T;T;T;T
Polyphen
P;P;P;.
Vest4
MutPred
Loss of MoRF binding (P = 0.0773);.;Loss of MoRF binding (P = 0.0773);.;
MVP
MPC
0.57
ClinPred
T
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