2-50925947-T-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001330078.2(NRXN1):c.781A>G(p.Asn261Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,574,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N261S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

NRXN1
NM_001330078.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 1.01

Publications

1 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)

NRXN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08790821).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRXN1	NM_001330078.2 link	c.781A>G	p.Asn261Asp	missense_variant	Exon 3 of 23	ENST00000401669.7	NP_001317007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRXN1	ENST00000401669.7 link	c.781A>G	p.Asn261Asp	missense_variant	Exon 3 of 23	5	NM_001330078.2	ENSP00000385017.2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151870

Hom.:

Cov.:

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000310

AC:

AN:

193702

AF XY:

0.0000390

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000727

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000111

AC:

158

AN:

1422402

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

703742

show subpopulations

African (AFR)

AF:

0.0000307

AC:

AN:

32558

American (AMR)

AF:

0.00

AC:

AN:

39316

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25284

East Asian (EAS)

AF:

0.00

AC:

AN:

37906

South Asian (SAS)

AF:

0.00

AC:

AN:

80792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

0.000143

AC:

156

AN:

1090596

Other (OTH)

AF:

0.0000170

AC:

AN:

58956

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151870

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74160

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41400

American (AMR)

AF:

0.00

AC:

AN:

15212

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000295

AC:

AN:

67882

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000901

Hom.:

Bravo

AF:

0.0000189

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.00000839

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Feb 15, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 19, 2015

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The N294D variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The N294D variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved across species, and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s). -

Inborn genetic diseases

Uncertain:1

Mar 13, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.880A>G (p.N294D) alteration is located in exon 4 (coding exon 3) of the NRXN1 gene. This alteration results from a A to G substitution at nucleotide position 880, causing the asparagine (N) at amino acid position 294 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Pitt-Hopkins-like syndrome 2

Uncertain:1

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 294 of the NRXN1 protein (p.Asn294Asp). This variant is present in population databases (rs781179797, gnomAD 0.006%). 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: 206211). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.014

.;T;.;.;T;.;.;T;T;.

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.27

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.75

T;T;T;T;T;T;T;D;D;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.088

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.69

N;N;.;.;.;.;.;.;.;.

PhyloP100

1.0

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.70

.;N;N;N;N;.;.;N;.;.

REVEL

Benign

0.043

Sift

Benign

0.66

.;T;T;T;T;.;.;T;.;.

Sift4G

Benign

0.60

T;T;T;T;T;T;T;T;.;T

Polyphen

0.039, 0.0020

.;B;B;.;.;.;.;.;.;.

Vest4

0.55

MVP

0.043

MPC

0.68

ClinPred

0.060

GERP RS

0.67

Varity_R

0.046

gMVP

0.45

Mutation Taster

=60/40

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over