chr2-50552698-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001330078.2(NRXN1):​c.1648C>T​(p.Leu550Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. L550V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

NRXN1
NM_001330078.2 missense

Scores

11
6
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.69

Publications

2 publications found
Variant links:
Genes affected
NRXN1 (HGNC:8008): (neurexin 1) This gene encodes a single-pass type I membrane protein that belongs to the neurexin family. Neurexins are cell-surface receptors that bind neuroligins to form Ca(2+)-dependent neurexin/neuroligin complexes at synapses in the central nervous system. This complex is required for efficient neurotransmission and is involved in the formation of synaptic contacts. Three members of this gene family have been studied in detail and are estimated to generate over 3,000 variants through the use of two alternative promoters (alpha and beta) and extensive alternative splicing in each family member. Recently, a third promoter (gamma) was identified for this gene in the 3' region. Mutations in this gene are associated with Pitt-Hopkins-like syndrome-2 and may contribute to susceptibility to schizophrenia. [provided by RefSeq, Aug 2016]
NRXN1 Gene-Disease associations (from GenCC):
  • complex neurodevelopmental disorder
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • chromosome 2p16.3 deletion syndrome
    Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • Pitt-Hopkins-like syndrome 2
    Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • autism
    Inheritance: AD Classification: MODERATE Submitted by: G2P
  • schizophrenia
    Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.867

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NRXN1NM_001330078.2 linkc.1648C>T p.Leu550Phe missense_variant Exon 9 of 23 ENST00000401669.7 NP_001317007.1 E7ERL8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NRXN1ENST00000401669.7 linkc.1648C>T p.Leu550Phe missense_variant Exon 9 of 23 5 NM_001330078.2 ENSP00000385017.2 E7ERL8

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152138
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
32
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152138
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74304
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41444
American (AMR)
AF:
0.00
AC:
0
AN:
15270
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.000193
AC:
1
AN:
5190
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4828
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10606
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68012
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.81
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.26
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.20
.;T;.;.;T;.;.;T
Eigen
Pathogenic
0.76
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.99
D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.16
D
MetaRNN
Pathogenic
0.87
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.72
D
MutationAssessor
Pathogenic
3.3
.;M;.;.;.;.;.;.
PhyloP100
5.7
PrimateAI
Pathogenic
0.83
D
PROVEAN
Uncertain
-3.3
.;D;D;D;D;.;.;N
REVEL
Pathogenic
0.82
Sift
Uncertain
0.0020
.;D;D;D;D;.;.;T
Sift4G
Uncertain
0.0020
D;D;D;D;D;D;D;D
Polyphen
1.0
.;.;D;.;.;.;.;.
Vest4
0.78
MutPred
0.74
.;Gain of catalytic residue at L550 (P = 0.0817);.;Gain of catalytic residue at L550 (P = 0.0817);.;.;.;.;
MVP
0.81
MPC
0.87
ClinPred
0.99
D
GERP RS
5.0
PromoterAI
-0.0066
Neutral
Varity_R
0.58
gMVP
0.75
Mutation Taster
=51/49
polymorphism

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

Other links and lift over

dbSNP: rs1295091945; hg19: chr2-50779836; API