2-50997951-C-T

Variant names:

• chr2-50997951-C-T
• rs12623467
• NM_001330078.2:c.772+29551G>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.772+29551G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 140,446 control chromosomes in the GnomAD database, including 3,500 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 0.12 (3500 hom., cov: 29)
• Consequence: NRXN1 NM_001330078.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.513
• 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: 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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.477 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.772+29551G>A		intron	N/A	NP_001317007.1	Q9ULB1-5
	NRXN1	NM_001135659.3		c.871+28420G>A		intron	N/A	NP_001129131.1	Q9ULB1-3
	NRXN1	NM_001330093.2		c.772+29551G>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.772+29551G>A		intron	N/A	ENSP00000385017.2	Q9ULB1-5
	NRXN1	ENST00000404971.5	TSL:1	c.871+28420G>A		intron	N/A	ENSP00000385142.1	Q9ULB1-3
	NRXN1	ENST00000625672.2	TSL:1	c.772+29551G>A		intron	N/A	ENSP00000485887.1	Q9ULB1-2

Frequencies

GnomAD3 genomes AF: 0.117 AC: 16449 AN: 140362 Hom.: 3481 Cov.: 29

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.269

Gnomad ASJ AF: 0.0596

Gnomad EAS AF: 0.493

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.0378

Gnomad MID AF: 0.134

Gnomad NFE AF: 0.0560

Gnomad OTH AF: 0.139

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

GnomAD4 genome AF: 0.117 AC: 16488 AN: 140446 Hom.: 3500 Cov.: 29 AF XY: 0.122 AC XY: 8348 AN XY: 68424

African (AFR) AF: 0.133 AC: 4411 AN: 33160

American (AMR) AF: 0.271 AC: 3922 AN: 14498

Ashkenazi Jewish (ASJ) AF: 0.0596 AC: 201 AN: 3372

East Asian (EAS) AF: 0.494 AC: 2401 AN: 4862

South Asian (SAS) AF: 0.230 AC: 1016 AN: 4418

European-Finnish (FIN) AF: 0.0378 AC: 389 AN: 10278

Middle Eastern (MID) AF: 0.130 AC: 37 AN: 284

European-Non Finnish (NFE) AF: 0.0560 AC: 3738 AN: 66754

Other (OTH) AF: 0.143 AC: 276 AN: 1930

Alfa AF: 0.0851 Hom.: 271

Asia WGS AF: 0.306 AC: 1022 AN: 3356

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.2
DANN	Benign	0.72
PhyloP100		-0.51
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: rs12623467; hg19: chr2-51225089;