chr2-50506555-G-A

Position:

chr2-50506555-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_001330078.2(NRXN1):c.2437C>T(p.Arg813Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,613,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

NRXN1
NM_001330078.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 8.05

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 links:

NRXN1 (HGNC:):

NRXN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.891

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRXN1	NM_001330078.2 linkuse as main transcript	c.2437C>T	p.Arg813Cys	missense_variant	13/23	ENST00000401669.7	NP_001317007.1	E7ERL8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRXN1	ENST00000401669.7 linkuse as main transcript	c.2437C>T	p.Arg813Cys	missense_variant	13/23	5	NM_001330078.2	ENSP00000385017.2		E7ERL8

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000805

AC:

AN:

248396

Hom.:

AF XY:

0.0000742

AC XY:

AN XY:

134746

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000169

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000154

AC:

225

AN:

1460998

Hom.:

Cov.:

AF XY:

0.000140

AC XY:

102

AN XY:

726766

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000194

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152094

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000131

Hom.:

Bravo

AF:

0.0000756

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000910

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000297

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Pitt-Hopkins-like syndrome 2

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 31, 2022	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 853 of the NRXN1 protein (p.Arg853Cys). This variant is present in population databases (rs201150987, gnomAD 0.02%). This missense change has been observed in individual(s) with neurodevelopmental disorders (PMID: 21424692, 33004838). This variant is also known as R813C. ClinVar contains an entry for this variant (Variation ID: 539874). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change does not substantially affect NRXN1 function (PMID: 21424692). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 21, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Jun 01, 2020	- -

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 26, 2024	PP3 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	This variant is associated with the following publications: (PMID: 21424692) -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 04, 2020

The c.2557C>T (p.R853C) alteration is located in exon 14 (coding exon 13) of the NRXN1 gene. This alteration results from a C to T substitution at nucleotide position 2557, causing the arginine (R) at amino acid position 853 to be replaced by a cysteine (C). Based on data from the Genome Aggregation Database (gnomAD) database, the NRXN1 c.2557C>T alteration was observed in 0.01% (22/279786) of total alleles studied, with a frequency of 0.02% (21/127956) in the European (non-Finnish) subpopulation. This alteration has been reported heterozygous as c.2437C>T (p.R813C) once from a cohort of patients with nonsyndromic intellectual disability. Inheritance was not determined. This alteration was also reported heterozygous in a patient with global developmental delay, hypotonia, toe syndactyly, micrognathia, and dysmorphic features as well as in the patient's father who had delay, hearing abnormalities, and learning difficulties. However, the proband also had a 1.18 Mb duplication of unknown significance (Deciphering Developmental Disorders Study, 2015; Gauthier, 2011). This amino acid position is highly conserved in available vertebrate species. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

NRXN1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 12, 2023

The NRXN1 c.2557C>T variant is predicted to result in the amino acid substitution p.Arg853Cys. Using an alternate transcript (NM_004801), this variant is also referred to in the literature as c.2437C>T (p.Arg813Cys aka R813C). This variant was reported in an individual with nonsyndromic intellectual disability (Supplementary Table 1, Gauthier et al. 2011. PubMed ID: 21424692). This variant was also identified in a large-scaler study analyzing risk genes for neurodevelopmental disorders, however limited data was provided (Supplementary Dataset 5, Wang et al. 2020. PubMed ID: 33004838). This variant was also identified in a Deciphering Developmental Disorders Study analyzing individuals with severe, undiagnosed, developmental disorders, however the variant was paternally inherited and the patient also carried a maternally inherited GLI2 variant (Supplementary Table 4, Deciphering Developmental Disorders Study. 2014. PubMed ID: 25533962). Of note, a functional study showed that this variant had similar function to that of controls (Gauthier et al. 2011. PubMed ID: 21424692). This variant is reported in 0.016% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-50733693-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.74

.;D;.;.;T;.;.;D

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.89

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.44

MutationAssessor

Pathogenic

3.0

.;M;.;.;.;.;.;.

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-6.2

.;D;D;D;.;.;.;.

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

.;D;D;D;.;.;.;.

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D

Polyphen

1.0

.;.;D;.;.;.;.;.

Vest4

0.89

MVP

0.38

MPC

1.0

ClinPred

0.79

GERP RS

5.7

Varity_R

0.72

gMVP

0.77

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over