rs78540316

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001330078.2(NRXN1):c.1285C>T(p.Pro429Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0034 in 1,609,946 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P429L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0031 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0034 ( 24 hom. )

Consequence

NRXN1
NM_001330078.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 10.0

Publications

15 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011325926).

BP6

Variant 2-50620057-G-A is Benign according to our data. Variant chr2-50620057-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00312 (475/152246) while in subpopulation NFE AF = 0.00332 (226/68026). AF 95% confidence interval is 0.00297. There are 1 homozygotes in GnomAd4. There are 260 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 24 AR,AD,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRXN1	NM_001330078.2 link	c.1285C>T	p.Pro429Ser	missense_variant	Exon 8 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.1285C>T	p.Pro429Ser	missense_variant	Exon 8 of 23	5	NM_001330078.2	ENSP00000385017.2

Frequencies

GnomAD3 genomes

AF:

0.00312

AC:

475

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000852

Gnomad ASJ

AF:

0.0130

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0143

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00332

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00373

AC:

915

AN:

245262

AF XY:

0.00362

show subpopulations

Gnomad AFR exome

AF:

0.000650

Gnomad AMR exome

AF:

0.000565

Gnomad ASJ exome

AF:

0.0143

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0155

Gnomad NFE exome

AF:

0.00306

Gnomad OTH exome

AF:

0.00525

GnomAD4 exome

AF:

0.00343

AC:

5004

AN:

1457700

Hom.:

Cov.:

AF XY:

0.00335

AC XY:

2426

AN XY:

725086

show subpopulations

African (AFR)

AF:

0.000360

AC:

AN:

33340

American (AMR)

AF:

0.00115

AC:

AN:

44328

Ashkenazi Jewish (ASJ)

AF:

0.0136

AC:

352

AN:

25920

East Asian (EAS)

AF:

0.00

AC:

AN:

39522

South Asian (SAS)

AF:

0.00151

AC:

129

AN:

85608

European-Finnish (FIN)

AF:

0.0149

AC:

795

AN:

53274

Middle Eastern (MID)

AF:

0.000349

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.00310

AC:

3438

AN:

1109770

Other (OTH)

AF:

0.00374

AC:

225

AN:

60200

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

235

471

706

942

1177

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

276

414

552

690

<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:

0.00312

AC:

475

AN:

152246

Hom.:

Cov.:

AF XY:

0.00349

AC XY:

260

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.000674

AC:

AN:

41558

American (AMR)

AF:

0.000851

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0130

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00145

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0143

AC:

152

AN:

10606

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00332

AC:

226

AN:

68026

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

124

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:

0.00274

Hom.:

Bravo

AF:

0.00197

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000508

AC:

ESP6500EA

AF:

0.00383

AC:

ExAC

AF:

0.00353

AC:

427

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Jun 11, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 03, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 19, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Feb 17, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pitt-Hopkins-like syndrome 2

Benign:3

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Jul 14, 2016

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 14, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NRXN1: BS2 -

Inborn genetic diseases

Benign:1

Jun 20, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

NRXN1-related disorder

Benign:1

Jun 06, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Benign

-0.080

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

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

Eigen

Uncertain

0.62

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

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

MetaRNN

Benign

0.011

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

MetaSVM

Benign

-0.48

MutationAssessor

Benign

1.4

.;L;.;.;.;.;.;.;.;.

PhyloP100

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-6.1

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

REVEL

Uncertain

0.43

Sift

Benign

0.087

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

Sift4G

Uncertain

0.0050

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

Polyphen

1.0

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

Vest4

0.74

MVP

0.51

MPC

0.89

ClinPred

0.034

GERP RS

6.2

PromoterAI

0.00030

Neutral

(source)

Varity_R

0.45

gMVP

0.49

Mutation Taster

=99/1

polymorphism

(source)

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

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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