2-50368718-G-C

Variant names:

• chr2-50368718-G-C
• rs13005521
• NM_001330078.2:c.3364+96724C>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.3364+96724C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 151,768 control chromosomes in the GnomAD database, including 6,150 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 0.27 (6150 hom., cov: 32)
• Consequence: NRXN1 NM_001330078.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.37
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.533 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.3364+96724C>G		intron	N/A	NP_001317007.1	Q9ULB1-5
	NRXN1	NM_001135659.3		c.3484+96724C>G		intron	N/A	NP_001129131.1	Q9ULB1-3
	NRXN1	NM_001330093.2		c.3361+96724C>G		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.3364+96724C>G		intron	N/A	ENSP00000385017.2	Q9ULB1-5
	NRXN1	ENST00000404971.5	TSL:1	c.3484+96724C>G		intron	N/A	ENSP00000385142.1	Q9ULB1-3
	NRXN1	ENST00000625672.2	TSL:1	c.3340+96724C>G		intron	N/A	ENSP00000485887.1	Q9ULB1-2

Frequencies

GnomAD3 genomes AF: 0.274 AC: 41574 AN: 151648 Hom.: 6133 Cov.: 32

Gnomad AFR AF: 0.291

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.183

Gnomad EAS AF: 0.550

Gnomad SAS AF: 0.277

Gnomad FIN AF: 0.295

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.244

Gnomad OTH AF: 0.283

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

GnomAD4 genome AF: 0.274 AC: 41635 AN: 151768 Hom.: 6150 Cov.: 32 AF XY: 0.277 AC XY: 20554 AN XY: 74168

African (AFR) AF: 0.291 AC: 12072 AN: 41438

American (AMR) AF: 0.278 AC: 4236 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 634 AN: 3466

East Asian (EAS) AF: 0.549 AC: 2824 AN: 5140

South Asian (SAS) AF: 0.277 AC: 1334 AN: 4822

European-Finnish (FIN) AF: 0.295 AC: 3117 AN: 10558

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.244 AC: 16567 AN: 67818

Other (OTH) AF: 0.290 AC: 610 AN: 2104

Alfa AF: 0.149 Hom.: 298

Bravo AF: 0.273

Asia WGS AF: 0.437 AC: 1519 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.15
DANN	Benign	0.43
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: rs13005521; hg19: chr2-50595856;