NM_001330078.2:c.3364+94665C>T

Variant names:

• chr2-50370777-G-A
• rs1915174
• NM_001330078.2:c.3364+94665C>T

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+94665C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.566 in 151,754 control chromosomes in the GnomAD database, including 26,550 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 0.57 (26550 hom., cov: 31)
• Consequence: NRXN1 NM_001330078.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.24
• Publications: 6 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=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.9 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRXN1	NM_001330078.2	c.3364+94665C>T		intron_variant	Intron 17 of 22	ENST00000401669.7	NP_001317007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRXN1	ENST00000401669.7	c.3364+94665C>T		intron_variant	Intron 17 of 22	5	NM_001330078.2	ENSP00000385017.2

Frequencies

GnomAD3 genomes AF: 0.566 AC: 85778 AN: 151636 Hom.: 26498 Cov.: 31

Gnomad AFR AF: 0.790

Gnomad AMI AF: 0.363

Gnomad AMR AF: 0.568

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.922

Gnomad SAS AF: 0.521

Gnomad FIN AF: 0.443

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.436

Gnomad OTH AF: 0.549

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

GnomAD4 genome AF: 0.566 AC: 85890 AN: 151754 Hom.: 26550 Cov.: 31 AF XY: 0.565 AC XY: 41926 AN XY: 74148

African (AFR) AF: 0.790 AC: 32760 AN: 41456

American (AMR) AF: 0.569 AC: 8642 AN: 15194

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 1363 AN: 3466

East Asian (EAS) AF: 0.922 AC: 4744 AN: 5144

South Asian (SAS) AF: 0.521 AC: 2506 AN: 4812

European-Finnish (FIN) AF: 0.443 AC: 4682 AN: 10566

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.436 AC: 29571 AN: 67804

Other (OTH) AF: 0.554 AC: 1168 AN: 2108

Alfa AF: 0.449 Hom.: 8372

Bravo AF: 0.592

Asia WGS AF: 0.721 AC: 2505 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.098
DANN	Benign	0.36
PhyloP100		-1.2
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: rs1915174; hg19: chr2-50597915;