rs17495366

Variant names:

• chr2-50041478-T-C
• rs17495366
• NM_001330078.2:c.4128+11793A>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.4128+11793A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 152,160 control chromosomes in the GnomAD database, including 3,726 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 0.19 (3726 hom., cov: 32)
• Consequence: NRXN1 NM_001330078.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.794
• Publications: 5 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=-0.79).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.273 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.4128+11793A>G		intron	N/A	NP_001317007.1
	NRXN1	NM_001135659.3		c.4248+11793A>G		intron	N/A	NP_001129131.1
	NRXN1	NM_001330093.2		c.4125+11793A>G		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.4128+11793A>G		intron	N/A	ENSP00000385017.2
	NRXN1	ENST00000404971.5	TSL:1	c.4248+11793A>G		intron	N/A	ENSP00000385142.1
	NRXN1	ENST00000625672.2	TSL:1	c.4104+11793A>G		intron	N/A	ENSP00000485887.1

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29143 AN: 152042 Hom.: 3727 Cov.: 32

Gnomad AFR AF: 0.0494

Gnomad AMI AF: 0.243

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.0630

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.277

Gnomad OTH AF: 0.185

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

GnomAD4 genome AF: 0.191 AC: 29127 AN: 152160 Hom.: 3726 Cov.: 32 AF XY: 0.190 AC XY: 14129 AN XY: 74370

African (AFR) AF: 0.0493 AC: 2048 AN: 41554

American (AMR) AF: 0.143 AC: 2191 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 913 AN: 3470

East Asian (EAS) AF: 0.0630 AC: 326 AN: 5178

South Asian (SAS) AF: 0.209 AC: 1009 AN: 4824

European-Finnish (FIN) AF: 0.299 AC: 3154 AN: 10560

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.277 AC: 18803 AN: 67972

Other (OTH) AF: 0.182 AC: 385 AN: 2112

Alfa AF: 0.245 Hom.: 3425

Bravo AF: 0.170

Asia WGS AF: 0.118 AC: 409 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.7
DANN	Benign	0.73
PhyloP100		0.79
Mutation Taster		=98/2	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: rs17495366; hg19: chr2-50268616;