rs199784139

Variant names:

• chr2-50497679-G-A
• rs199784139
• NM_001330078.2:c.2533C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP3 BP4 BS1_Supporting BS2

The NM_001330078.2(NRXN1):​c.2533C>T​(p.His845Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.001 in 1,613,558 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H845R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (2 hom.)
• Consequence: NRXN1 NM_001330078.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13 B:1 O:1
• Conservation: PhyloP100: 9.76
• Publications: 13 publications found

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)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: BayesDel_noAF, Cadd, Eigen, M_CAP, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationAssessor, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.3581644).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000611 (93/152222) while in subpopulation NFE AF = 0.00115 (78/68016). AF 95% confidence interval is 0.000941. There are 0 homozygotes in GnomAd4. There are 32 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330078.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN1	NM_001330078.2	MANE Select	c.2533C>T	p.His845Tyr	missense	Exon 14 of 23	NP_001317007.1
	NRXN1	NM_001135659.3		c.2653C>T	p.His885Tyr	missense	Exon 15 of 24	NP_001129131.1
	NRXN1	NM_001330093.2		c.2530C>T	p.His844Tyr	missense	Exon 14 of 23	NP_001317022.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN1	ENST00000401669.7	TSL:5 MANE Select	c.2533C>T	p.His845Tyr	missense	Exon 14 of 23	ENSP00000385017.2
	NRXN1	ENST00000404971.5	TSL:1	c.2653C>T	p.His885Tyr	missense	Exon 15 of 24	ENSP00000385142.1
	NRXN1	ENST00000625672.2	TSL:1	c.2509C>T	p.His837Tyr	missense	Exon 12 of 21	ENSP00000485887.1

Frequencies

GnomAD3 genomes AF: 0.000611 AC: 93 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00115

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000507 AC: 126 AN: 248370 AF XY: 0.000542

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.00104 AC: 1527 AN: 1461336 Hom.: 2 Cov.: 31 AF XY: 0.00101 AC XY: 735 AN XY: 726904

African (AFR) AF: 0.000448 AC: 15 AN: 33474

American (AMR) AF: 0.0000224 AC: 1 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86230

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53392

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.00132 AC: 1470 AN: 1111582

Other (OTH) AF: 0.000563 AC: 34 AN: 60362

GnomAD4 genome AF: 0.000611 AC: 93 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74438

African (AFR) AF: 0.000313 AC: 13 AN: 41518

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00115 AC: 78 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000953 Hom.: 0

Bravo AF: 0.000563

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00145 AC: 12

ExAC AF: 0.000596 AC: 72

EpiCase AF: 0.000983

EpiControl AF: 0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:13 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:6

Dec 14, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 25, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in a patient with autism spectrum disorder, sibling with learning disabilities and their unaffected father, and in an unrelated individual with spastic paraplegia and epilepsy who was also a compound heterozygote for 2 variants in the ALDH18A1 gene (PMID: 23849776, 29754261); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variant in a gene in which most reported pathogenic variants are truncating/loss-of-function; This variant is associated with the following publications: (PMID: 29754261, 34168285, 23849776, 40223535)

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 04, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Pitt-Hopkins-like syndrome 2 Uncertain:3 Benign:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Jun 28, 2018

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

Jun 11, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Pitt-Hopkins-like syndrome 2;C3808494:Chromosome 2p16.3 deletion syndrome Uncertain:2 Other:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GenomeConnect-Association for Creatine Deficiencies, Association for Creatine Deficiencies

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Uncertain significance and reported on 07-13-2019 by lab or GTR ID 26957. GenomeConnect - Association for Creatine Deficiencies assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NRXN1 NM_001135659.2 exon 15 p.His885Tyr (c.2653C>T): This variant has been reported in the literature in at least 1 individual with autism spectrum disorder (ASD), segregating with disease in 1 affected family member. However, this family member did not meet clinical criteria for ASD (Jiang 2013 PMID:23849776). This variant is present in 0.1% (78/68024) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/2-50497679-G-A?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:20245). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

not specified Uncertain:1

Sep 22, 2015

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Uncertain:1

Jul 20, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2653C>T (p.H885Y) alteration is located in exon 15 (coding exon 14) of the NRXN1 gene. This alteration results from a C to T substitution at nucleotide position 2653, causing the histidine (H) at amino acid position 885 to be replaced by a tyrosine (Y). The alteration is ultra rare in population databases:_x000D_ The NRXN1 c.2653C>T alteration was observed in 72 out of 120,252 total alleles studied (0.06%) in the Exome Aggregation Consortium (ExAC) database, with a frequency of 69/66,496 (0.1%) in the European (Non-Finnish) sub-population. Based on data from the NHLBI Exome Sequencing Project (ESP), the NRXN1 c.2653C>T alteration was observed in 12 among 12,074 total alleles studied (0.1%). Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project. Rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012; please note that some variants may appear to be rare due to ethnic underrepresentation in the database)._x000D_ IF USED, PULL THESE INTO REFERENCES:_x000D_ Kryukov GV, et al. (2007) Am J Hum Genet 80:727-739. Tennessen JA, et al. (2012) Science 337(64):64-69. The alteration has been observed in affected individuals: _x000D_ The NRXN1 c.2653C>T (p.H885Y) alteration has been reported in a proband with autism spectrum disorder and his brother with a learning disability. The alteration was found to be inherited from the brothers' unaffected father (Jiang, 2013). The altered amino acid is conserved throughout evolution:_x000D_ The p.H885 amino acid is conserved in available vertebrate species. In silico prediction is conflicting:_x000D_ The p.H885Y alteration is predicted to be probably damaging by Polyphen and tolerated by SIFT in silico analyses. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.3	L
PhyloP100		9.8
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.4	D
REVEL	Pathogenic	0.71
Sift	Benign	0.094	T
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.94
MVP		0.24
MPC		0.65
ClinPred		0.19	T
GERP RS		6.0
Varity_R		0.53
gMVP		0.69
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs199784139; hg19: chr2-50724817; COSMIC: COSV58446083; COSMIC: COSV58446083;