NM_001330078.2:c.4129-35803A>G

Variant names:

• chr2-49979594-T-C
• rs2882594
• NM_001330078.2:c.4129-35803A>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.4129-35803A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.492 in 151,934 control chromosomes in the GnomAD database, including 18,834 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 0.49 (18834 hom., cov: 32)
• Consequence: NRXN1 NM_001330078.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.122
• 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: 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=-0.83).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.535 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRXN1	NM_001330078.2	c.4129-35803A>G		intron_variant	Intron 21 of 22	ENST00000401669.7	NP_001317007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRXN1	ENST00000401669.7	c.4129-35803A>G		intron_variant	Intron 21 of 22	5	NM_001330078.2	ENSP00000385017.2

Frequencies

GnomAD3 genomes AF: 0.492 AC: 74720 AN: 151814 Hom.: 18832 Cov.: 32

Gnomad AFR AF: 0.435

Gnomad AMI AF: 0.686

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.649

Gnomad EAS AF: 0.303

Gnomad SAS AF: 0.551

Gnomad FIN AF: 0.516

Gnomad MID AF: 0.637

Gnomad NFE AF: 0.539

Gnomad OTH AF: 0.506

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

GnomAD4 genome AF: 0.492 AC: 74758 AN: 151934 Hom.: 18834 Cov.: 32 AF XY: 0.491 AC XY: 36449 AN XY: 74248

African (AFR) AF: 0.435 AC: 18019 AN: 41416

American (AMR) AF: 0.413 AC: 6307 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.649 AC: 2251 AN: 3466

East Asian (EAS) AF: 0.304 AC: 1561 AN: 5138

South Asian (SAS) AF: 0.550 AC: 2649 AN: 4814

European-Finnish (FIN) AF: 0.516 AC: 5434 AN: 10534

Middle Eastern (MID) AF: 0.637 AC: 186 AN: 292

European-Non Finnish (NFE) AF: 0.540 AC: 36668 AN: 67966

Other (OTH) AF: 0.501 AC: 1057 AN: 2110

Alfa AF: 0.395 Hom.: 1143

Bravo AF: 0.476

Asia WGS AF: 0.385 AC: 1341 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.8
DANN	Benign	0.71
PhyloP100		0.12
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: rs2882594; hg19: chr2-50206732;