rs1882296

Variant names:

• chr2-50039707-T-C
• rs1882296
• NM_001330078.2:c.4128+13564A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001330078.2(NRXN1):​c.4128+13564A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 151,942 control chromosomes in the GnomAD database, including 11,708 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.38 (11708 hom., cov: 32)
• Consequence: NRXN1 NM_001330078.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.133
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.422 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRXN1	NM_001330078.2	c.4128+13564A>G		intron_variant	Intron 21 of 22	ENST00000401669.7	NP_001317007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRXN1	ENST00000401669.7	c.4128+13564A>G		intron_variant	Intron 21 of 22	5	NM_001330078.2	ENSP00000385017.2

Frequencies

GnomAD3 genomes AF: 0.383 AC: 58142 AN: 151824 Hom.: 11695 Cov.: 32

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.493

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.446

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.311

Gnomad FIN AF: 0.396

Gnomad MID AF: 0.510

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.371

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.383 AC: 58180 AN: 151942 Hom.: 11708 Cov.: 32 AF XY: 0.377 AC XY: 28024 AN XY: 74282

African (AFR) AF: 0.377 AC: 15596 AN: 41418

American (AMR) AF: 0.292 AC: 4451 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.446 AC: 1547 AN: 3468

East Asian (EAS) AF: 0.110 AC: 570 AN: 5160

South Asian (SAS) AF: 0.309 AC: 1491 AN: 4828

European-Finnish (FIN) AF: 0.396 AC: 4171 AN: 10546

Middle Eastern (MID) AF: 0.514 AC: 148 AN: 288

European-Non Finnish (NFE) AF: 0.426 AC: 28983 AN: 67958

Other (OTH) AF: 0.367 AC: 776 AN: 2116

Alfa AF: 0.409 Hom.: 16900

Bravo AF: 0.371

Asia WGS AF: 0.212 AC: 737 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.6
DANN	Benign	0.54
PhyloP100		-0.13
Mutation Taster		=100/0	polymorphism (auto)

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: rs1882296; hg19: chr2-50266845;