rs1254204827

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_015080.4(NRXN2):​c.4684G>T​(p.Ala1562Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000729 in 1,372,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1562T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)
Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

NRXN2
NM_015080.4 missense

Scores

2
5
12

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.52
Variant links:
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 Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.27994338).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NRXN2NM_015080.4 linkc.4684G>T p.Ala1562Ser missense_variant Exon 23 of 23 ENST00000265459.11 NP_055895.1 Q9P2S2-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NRXN2ENST00000265459.11 linkc.4684G>T p.Ala1562Ser missense_variant Exon 23 of 23 5 NM_015080.4 ENSP00000265459.5 Q9P2S2-1
NRXN2ENST00000704782.1 linkc.4693G>T p.Ala1565Ser missense_variant Exon 22 of 22 ENSP00000516031.1 A0A994J5C3
NRXN2ENST00000704781.1 linkc.4262-151G>T intron_variant Intron 21 of 21 ENSP00000516029.1 A0A994J4N8

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD4 exome
AF:
7.29e-7
AC:
1
AN:
1372660
Hom.:
0
Cov.:
33
AF XY:
0.00000148
AC XY:
1
AN XY:
674758
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.38e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.25
BayesDel_addAF
Benign
-0.054
T
BayesDel_noAF
Benign
-0.32
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.22
T;T;.;T;.
Eigen
Benign
0.18
Eigen_PC
Benign
0.15
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D;.;D;D;D
M_CAP
Uncertain
0.17
D
MetaRNN
Benign
0.28
T;T;T;T;T
MetaSVM
Uncertain
-0.25
T
MutationAssessor
Benign
1.4
.;L;.;L;.
PrimateAI
Pathogenic
0.85
D
PROVEAN
Benign
-1.5
N;N;N;N;N
REVEL
Benign
0.20
Sift
Uncertain
0.0050
D;D;D;D;D
Sift4G
Benign
0.17
T;T;T;T;T
Polyphen
1.0
D;B;B;B;.
Vest4
0.31
MutPred
0.099
.;Gain of glycosylation at A1562 (P = 0.0019);.;Gain of glycosylation at A1562 (P = 0.0019);.;
MVP
0.65
MPC
0.97
ClinPred
0.91
D
GERP RS
3.4
Varity_R
0.15
gMVP
0.24

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-64375123; API