rs796052776
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001330078.2(NRXN1):c.2564G>A(p.Arg855Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,530 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
NRXN1
NM_001330078.2 missense
NM_001330078.2 missense
Scores
2
9
3
Clinical Significance
Conservation
PhyloP100: 5.47
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NRXN1 | NM_001330078.2 | c.2564G>A | p.Arg855Gln | missense_variant | 14/23 | ENST00000401669.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NRXN1 | ENST00000401669.7 | c.2564G>A | p.Arg855Gln | missense_variant | 14/23 | 5 | NM_001330078.2 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461530Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727064
GnomAD4 exome
AF:
AC:
3
AN:
1461530
Hom.:
Cov.:
31
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AC XY:
3
AN XY:
727064
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
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:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 21, 2022 | Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. ClinVar contains an entry for this variant (Variation ID: 206247). This missense change has been observed in individual(s) with neurodevelopmental disorder (PMID: 33004838). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 895 of the NRXN1 protein (p.Arg895Gln). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues | Feb 07, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
N;N;N;N;N;N
PrimateAI
Uncertain
T
Sift4G
Uncertain
D;D;D;D;D;D;D;D
Polyphen
0.99
.;.;D;.;.;.;.;.
Vest4
MutPred
0.60
.;Gain of sheet (P = 0.1945);.;Gain of sheet (P = 0.1945);.;.;.;.;
MVP
MPC
0.56
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at