2-50538274-G-T

Variant names:

• chr2-50538274-G-T
• rs56086732
• NM_001330078.2:c.2122C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001330078.2(NRXN1):​c.2122C>A​(p.Leu708Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00499 in 1,612,464 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (28 hom.)
• Consequence: NRXN1 NM_001330078.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.92
• Publications: 18 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014493406).
• BP6: Variant 2-50538274-G-T is Benign according to our data. Variant chr2-50538274-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00446 (679/152296) while in subpopulation AMR AF = 0.007 (107/15290). AF 95% confidence interval is 0.00604. There are 3 homozygotes in GnomAd4. There are 333 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.2122C>A	p.Leu708Ile	missense	Exon 10 of 23	NP_001317007.1
	NRXN1	NM_001135659.3		c.2242C>A	p.Leu748Ile	missense	Exon 11 of 24	NP_001129131.1
	NRXN1	NM_001330093.2		c.2119C>A	p.Leu707Ile	missense	Exon 10 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.2122C>A	p.Leu708Ile	missense	Exon 10 of 23	ENSP00000385017.2
	NRXN1	ENST00000404971.5	TSL:1	c.2242C>A	p.Leu748Ile	missense	Exon 11 of 24	ENSP00000385142.1
	NRXN1	ENST00000625672.2	TSL:1	c.2098C>A	p.Leu700Ile	missense	Exon 8 of 21	ENSP00000485887.1

Frequencies

GnomAD3 genomes AF: 0.00446 AC: 679 AN: 152178 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00701

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00622

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00654

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00384 AC: 954 AN: 248338 AF XY: 0.00395

Gnomad AFR exome AF: 0.000840

Gnomad AMR exome AF: 0.00325

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00554

Gnomad NFE exome AF: 0.00569

Gnomad OTH exome AF: 0.00381

GnomAD4 exome AF: 0.00505 AC: 7373 AN: 1460168 Hom.: 28 Cov.: 31 AF XY: 0.00506 AC XY: 3675 AN XY: 726064

African (AFR) AF: 0.000688 AC: 23 AN: 33446

American (AMR) AF: 0.00362 AC: 162 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00138 AC: 119 AN: 86182

European-Finnish (FIN) AF: 0.00497 AC: 265 AN: 53370

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5762

European-Non Finnish (NFE) AF: 0.00585 AC: 6494 AN: 1110642

Other (OTH) AF: 0.00489 AC: 295 AN: 60316

GnomAD4 genome AF: 0.00446 AC: 679 AN: 152296 Hom.: 3 Cov.: 32 AF XY: 0.00447 AC XY: 333 AN XY: 74472

African (AFR) AF: 0.00101 AC: 42 AN: 41568

American (AMR) AF: 0.00700 AC: 107 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.00622 AC: 66 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00654 AC: 445 AN: 68018

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00499 Hom.: 12

Bravo AF: 0.00412

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00101 AC: 4

ESP6500EA AF: 0.00722 AC: 60

ExAC AF: 0.00388 AC: 469

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00649

EpiControl AF: 0.00760

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Jul 13, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 30, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 30, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23769996, 28289584, 18179900, 21288692, 18728070, 23935565)

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NRXN1: BS2

not specified Benign:2

Jul 25, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 23, 2015

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Pitt-Hopkins-like syndrome 2 Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Inborn genetic diseases Benign:1

Sep 22, 2021

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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	0.28	N
PhyloP100		4.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.30
Sift	Benign	0.30	T
Sift4G	Benign	0.21	T
Polyphen		0.57	P
Vest4		0.51
MVP		0.41
MPC		0.64
ClinPred		0.010	T
GERP RS		5.1
Varity_R		0.27
gMVP		0.22
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs56086732; hg19: chr2-50765412; COSMIC: COSV58453863; COSMIC: COSV58453863;