rs2123388

Variant names:

• chr2-50086146-G-T
• rs2123388
• NM_001330078.2:c.3718+5177C>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.3718+5177C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 151,984 control chromosomes in the GnomAD database, including 5,673 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 0.26 (5673 hom., cov: 32)
• Consequence: NRXN1 NM_001330078.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.585
• Publications: 0 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: Ambry Genetics, G2P, 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.379 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN1	NM_001330078.2	MANE Select	c.3718+5177C>A		intron	N/A	NP_001317007.1	Q9ULB1-5
	NRXN1	NM_001135659.3		c.3838+5177C>A		intron	N/A	NP_001129131.1	Q9ULB1-3
	NRXN1	NM_001330093.2		c.3715+5177C>A		intron	N/A	NP_001317022.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN1	ENST00000401669.7	TSL:5 MANE Select	c.3718+5177C>A		intron	N/A	ENSP00000385017.2	Q9ULB1-5
	NRXN1	ENST00000404971.5	TSL:1	c.3838+5177C>A		intron	N/A	ENSP00000385142.1	Q9ULB1-3
	NRXN1	ENST00000625672.2	TSL:1	c.3694+5177C>A		intron	N/A	ENSP00000485887.1	Q9ULB1-2

Frequencies

GnomAD3 genomes AF: 0.264 AC: 40058 AN: 151866 Hom.: 5658 Cov.: 32

Gnomad AFR AF: 0.269

Gnomad AMI AF: 0.458

Gnomad AMR AF: 0.386

Gnomad ASJ AF: 0.311

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.276

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.237

Gnomad OTH AF: 0.278

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

GnomAD4 genome AF: 0.264 AC: 40112 AN: 151984 Hom.: 5673 Cov.: 32 AF XY: 0.264 AC XY: 19585 AN XY: 74286

African (AFR) AF: 0.269 AC: 11167 AN: 41456

American (AMR) AF: 0.387 AC: 5909 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 1079 AN: 3466

East Asian (EAS) AF: 0.361 AC: 1864 AN: 5158

South Asian (SAS) AF: 0.275 AC: 1324 AN: 4816

European-Finnish (FIN) AF: 0.146 AC: 1544 AN: 10568

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.237 AC: 16129 AN: 67940

Other (OTH) AF: 0.278 AC: 586 AN: 2110

Alfa AF: 0.235 Hom.: 589

Bravo AF: 0.289

Asia WGS AF: 0.271 AC: 945 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.67
DANN	Benign	0.36
PhyloP100		-0.58
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: rs2123388; hg19: chr2-50313284;