NM_001330078.2:c.833-135375A>G

Variant names:

• chr2-50758990-T-C
• rs10445932
• NM_001330078.2:c.833-135375A>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.833-135375A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0789 in 151,912 control chromosomes in the GnomAD database, including 609 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 0.079 (609 hom., cov: 32)
• Consequence: NRXN1 NM_001330078.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0240
• Publications: 1 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=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

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.833-135375A>G		intron	N/A	NP_001317007.1
	NRXN1	NM_001135659.3		c.932-135375A>G		intron	N/A	NP_001129131.1
	NRXN1	NM_001330093.2		c.830-135375A>G		intron	N/A	NP_001317022.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN1	ENST00000401669.7	TSL:5 MANE Select	c.833-135375A>G		intron	N/A	ENSP00000385017.2
	NRXN1	ENST00000404971.5	TSL:1	c.932-135375A>G		intron	N/A	ENSP00000385142.1
	NRXN1	ENST00000625672.2	TSL:1	c.833-135375A>G		intron	N/A	ENSP00000485887.1

Frequencies

GnomAD3 genomes AF: 0.0790 AC: 11987 AN: 151794 Hom.: 610 Cov.: 32

Gnomad AFR AF: 0.0206

Gnomad AMI AF: 0.0859

Gnomad AMR AF: 0.0717

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.0691

Gnomad SAS AF: 0.0846

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.0987

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

GnomAD4 genome AF: 0.0789 AC: 11983 AN: 151912 Hom.: 609 Cov.: 32 AF XY: 0.0800 AC XY: 5937 AN XY: 74258

African (AFR) AF: 0.0206 AC: 853 AN: 41490

American (AMR) AF: 0.0716 AC: 1091 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 468 AN: 3464

East Asian (EAS) AF: 0.0687 AC: 352 AN: 5122

South Asian (SAS) AF: 0.0845 AC: 408 AN: 4830

European-Finnish (FIN) AF: 0.106 AC: 1125 AN: 10588

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.108 AC: 7357 AN: 67864

Other (OTH) AF: 0.0981 AC: 207 AN: 2110

Alfa AF: 0.0910 Hom.: 440

Bravo AF: 0.0732

Asia WGS AF: 0.0570 AC: 199 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.1
DANN	Benign	0.78
PhyloP100		-0.024
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: rs10445932; hg19: chr2-50986128;