NM_001330078.2:c.832+69525A>G

Variant names:

• chr2-50852344-T-C
• rs2193225
• NM_001330078.2:c.832+69525A>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.832+69525A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.413 in 152,106 control chromosomes in the GnomAD database, including 14,592 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 0.41 (14592 hom., cov: 33)
• Consequence: NRXN1 NM_001330078.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.43
• Publications: 8 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=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.544 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.832+69525A>G		intron	N/A	NP_001317007.1
	NRXN1	NM_001135659.3		c.931+69525A>G		intron	N/A	NP_001129131.1
	NRXN1	NM_001330093.2		c.829+69525A>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.832+69525A>G		intron	N/A	ENSP00000385017.2
	NRXN1	ENST00000404971.5	TSL:1	c.931+69525A>G		intron	N/A	ENSP00000385142.1
	NRXN1	ENST00000625672.2	TSL:1	c.832+69525A>G		intron	N/A	ENSP00000485887.1

Frequencies

GnomAD3 genomes AF: 0.413 AC: 62789 AN: 151988 Hom.: 14597 Cov.: 33

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.367

Gnomad ASJ AF: 0.563

Gnomad EAS AF: 0.176

Gnomad SAS AF: 0.367

Gnomad FIN AF: 0.430

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.549

Gnomad OTH AF: 0.425

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

GnomAD4 genome AF: 0.413 AC: 62778 AN: 152106 Hom.: 14592 Cov.: 33 AF XY: 0.404 AC XY: 30061 AN XY: 74348

African (AFR) AF: 0.224 AC: 9298 AN: 41474

American (AMR) AF: 0.366 AC: 5601 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.563 AC: 1953 AN: 3472

East Asian (EAS) AF: 0.175 AC: 908 AN: 5180

South Asian (SAS) AF: 0.368 AC: 1773 AN: 4824

European-Finnish (FIN) AF: 0.430 AC: 4545 AN: 10576

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.548 AC: 37279 AN: 67970

Other (OTH) AF: 0.423 AC: 895 AN: 2116

Alfa AF: 0.493 Hom.: 61537

Bravo AF: 0.396

Asia WGS AF: 0.282 AC: 980 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.27
DANN	Benign	0.38
PhyloP100		-1.4
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: rs2193225; hg19: chr2-51079482;