2-51024999-A-G

Variant names:

• chr2-51024999-A-G
• rs1558852
• NM_001330078.2:c.772+2503T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001330078.2(NRXN1):​c.772+2503T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 152,030 control chromosomes in the GnomAD database, including 4,630 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 0.23 (4630 hom., cov: 32)
• Consequence: NRXN1 NM_001330078.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.940
• 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: 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.434 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.772+2503T>C		intron	N/A	NP_001317007.1
	NRXN1	NM_001135659.3		c.871+1372T>C		intron	N/A	NP_001129131.1
	NRXN1	NM_001330093.2		c.772+2503T>C		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.772+2503T>C		intron	N/A	ENSP00000385017.2
	NRXN1	ENST00000404971.5	TSL:1	c.871+1372T>C		intron	N/A	ENSP00000385142.1
	NRXN1	ENST00000625672.2	TSL:1	c.772+2503T>C		intron	N/A	ENSP00000485887.1

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35318 AN: 151912 Hom.: 4600 Cov.: 32

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.289

Gnomad AMR AF: 0.399

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.448

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.205

Gnomad OTH AF: 0.225

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

GnomAD4 genome AF: 0.233 AC: 35386 AN: 152030 Hom.: 4630 Cov.: 32 AF XY: 0.237 AC XY: 17635 AN XY: 74302

African (AFR) AF: 0.187 AC: 7763 AN: 41498

American (AMR) AF: 0.400 AC: 6118 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 640 AN: 3472

East Asian (EAS) AF: 0.450 AC: 2315 AN: 5150

South Asian (SAS) AF: 0.337 AC: 1624 AN: 4824

European-Finnish (FIN) AF: 0.205 AC: 2165 AN: 10564

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.205 AC: 13953 AN: 67932

Other (OTH) AF: 0.228 AC: 480 AN: 2106

Alfa AF: 0.215 Hom.: 10281

Bravo AF: 0.246

Asia WGS AF: 0.364 AC: 1263 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	13
DANN	Benign	0.72
PhyloP100		0.94
Mutation Taster		=99/1	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: rs1558852; hg19: chr2-51252137;