NM_001330078.2:c.2498-1619C>T

Variant names:

• chr2-50499333-G-A
• rs17476669
• NM_001330078.2:c.2498-1619C>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.2498-1619C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 151,862 control chromosomes in the GnomAD database, including 8,888 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 0.31 (8888 hom., cov: 31)
• Consequence: NRXN1 NM_001330078.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.430
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.404 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.2498-1619C>T		intron	N/A	NP_001317007.1
	NRXN1	NM_001135659.3		c.2618-1619C>T		intron	N/A	NP_001129131.1
	NRXN1	NM_001330093.2		c.2495-1619C>T		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.2498-1619C>T		intron	N/A	ENSP00000385017.2
	NRXN1	ENST00000404971.5	TSL:1	c.2618-1619C>T		intron	N/A	ENSP00000385142.1
	NRXN1	ENST00000625672.2	TSL:1	c.2474-1619C>T		intron	N/A	ENSP00000485887.1

Frequencies

GnomAD3 genomes AF: 0.314 AC: 47706 AN: 151744 Hom.: 8887 Cov.: 31

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.468

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.479

Gnomad EAS AF: 0.0848

Gnomad SAS AF: 0.354

Gnomad FIN AF: 0.465

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.408

Gnomad OTH AF: 0.337

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

GnomAD4 genome AF: 0.314 AC: 47705 AN: 151862 Hom.: 8888 Cov.: 31 AF XY: 0.314 AC XY: 23275 AN XY: 74202

African (AFR) AF: 0.139 AC: 5765 AN: 41448

American (AMR) AF: 0.278 AC: 4231 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.479 AC: 1661 AN: 3470

East Asian (EAS) AF: 0.0846 AC: 436 AN: 5156

South Asian (SAS) AF: 0.355 AC: 1708 AN: 4812

European-Finnish (FIN) AF: 0.465 AC: 4888 AN: 10502

Middle Eastern (MID) AF: 0.524 AC: 154 AN: 294

European-Non Finnish (NFE) AF: 0.408 AC: 27733 AN: 67916

Other (OTH) AF: 0.334 AC: 704 AN: 2110

Alfa AF: 0.378 Hom.: 19302

Bravo AF: 0.287

Asia WGS AF: 0.212 AC: 738 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	8.8
DANN	Benign	0.74
PhyloP100		0.43
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: rs17476669; hg19: chr2-50726471;