2-50236928-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_001330078.2(NRXN1):​c.3407C>T​(p.Thr1136Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000465 in 1,613,360 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T1136T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

NRXN1
NM_001330078.2 missense

Scores

2
9
8

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.86
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.36300197).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NRXN1NM_001330078.2 linkuse as main transcriptc.3407C>T p.Thr1136Met missense_variant 18/23 ENST00000401669.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NRXN1ENST00000401669.7 linkuse as main transcriptc.3407C>T p.Thr1136Met missense_variant 18/235 NM_001330078.2 A1

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152058
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:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.0000943
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000112
AC:
28
AN:
250494
Hom.:
0
AF XY:
0.000111
AC XY:
15
AN XY:
135352
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 SAS exome
AF:
0.000327
Gnomad FIN exome
AF:
0.000139
Gnomad NFE exome
AF:
0.000133
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000465
AC:
68
AN:
1461184
Hom.:
0
Cov.:
32
AF XY:
0.0000550
AC XY:
40
AN XY:
726914
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000139
Gnomad4 FIN exome
AF:
0.000150
Gnomad4 NFE exome
AF:
0.0000396
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152176
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74370
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.0000943
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000415
Hom.:
0
Bravo
AF:
0.0000529
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000124
AC:
15
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Pitt-Hopkins-like syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 27, 2023This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1176 of the NRXN1 protein (p.Thr1176Met). This variant is present in population databases (rs138261348, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with NRXN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 206265). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NRXN1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Pitt-Hopkins-like syndrome 2;C3808494:Chromosome 2p16.3 deletion syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Uncertain
0.095
D
BayesDel_noAF
Pathogenic
0.20
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.13
.;T;.;.;D;.;.;T;.;T
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.61
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D;D;D;D;D;D;D;D;D;D
M_CAP
Benign
0.030
D
MetaRNN
Benign
0.36
T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
-0.24
T
MutationAssessor
Benign
1.9
.;.;.;L;L;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.78
T
PROVEAN
Uncertain
-3.1
.;D;D;D;.;D;.;.;.;.
REVEL
Uncertain
0.44
Sift
Benign
0.089
.;T;T;T;.;T;.;.;.;.
Sift4G
Benign
0.064
T;T;T;T;T;T;T;T;T;.
Polyphen
0.94, 0.98
.;.;P;.;D;.;.;.;.;.
Vest4
0.41
MVP
0.20
MPC
0.75
ClinPred
0.22
T
GERP RS
5.7
Varity_R
0.11
gMVP
0.58

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs138261348; hg19: chr2-50464066; API