rs10490227

Variant names:

• chr2-50432377-C-T
• rs10490227
• NM_001330078.2:c.3364+33065G>A

Variant summary

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

The NM_001330078.2(NRXN1):​c.3364+33065G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 152,172 control chromosomes in the GnomAD database, including 2,817 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 0.17 (2817 hom., cov: 32)
  • Exomes 𝑓: 0.10 (0 hom.)
• Consequence: NRXN1 NM_001330078.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.329
• Publications: 3 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.506 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.3364+33065G>A		intron	N/A	NP_001317007.1
	NRXN1	NM_001135659.3		c.3484+33065G>A		intron	N/A	NP_001129131.1
	NRXN1	NM_001330093.2		c.3361+33065G>A		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.3364+33065G>A		intron	N/A	ENSP00000385017.2
	NRXN1	ENST00000404971.5	TSL:1	c.3484+33065G>A		intron	N/A	ENSP00000385142.1
	NRXN1	ENST00000625672.2	TSL:1	c.3340+33065G>A		intron	N/A	ENSP00000485887.1

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25554 AN: 152044 Hom.: 2815 Cov.: 32

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.523

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.166

GnomAD4 exome AF: 0.100 AC: 1 AN: 10 Hom.: 0 AF XY: 0.167 AC XY: 1 AN XY: 6

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.250 AC: 1 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 4

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.168 AC: 25571 AN: 152162 Hom.: 2817 Cov.: 32 AF XY: 0.171 AC XY: 12716 AN XY: 74398

African (AFR) AF: 0.231 AC: 9569 AN: 41502

American (AMR) AF: 0.221 AC: 3382 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 407 AN: 3472

East Asian (EAS) AF: 0.523 AC: 2696 AN: 5158

South Asian (SAS) AF: 0.186 AC: 895 AN: 4820

European-Finnish (FIN) AF: 0.110 AC: 1163 AN: 10594

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.104 AC: 7049 AN: 68018

Other (OTH) AF: 0.169 AC: 357 AN: 2112

Alfa AF: 0.132 Hom.: 7596

Bravo AF: 0.185

Asia WGS AF: 0.340 AC: 1185 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.9
DANN	Benign	0.71
PhyloP100		-0.33
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: rs10490227; hg19: chr2-50659515;