chr2-50336767-T-G

Variant names:

• chr2-50336767-T-G
• rs9309181
• NM_001330078.2:c.3365-99797A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001330078.2(NRXN1):​c.3365-99797A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 152,046 control chromosomes in the GnomAD database, including 13,570 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 0.37 (13570 hom., cov: 32)
• Consequence: NRXN1 NM_001330078.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.970
• Publications: 2 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)

ENSG00000285548 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.678 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.3365-99797A>C		intron	N/A	NP_001317007.1
	NRXN1	NM_001135659.3		c.3485-99797A>C		intron	N/A	NP_001129131.1
	NRXN1	NM_001330093.2		c.3362-99797A>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.3365-99797A>C		intron	N/A	ENSP00000385017.2
	NRXN1	ENST00000404971.5	TSL:1	c.3485-99797A>C		intron	N/A	ENSP00000385142.1
	NRXN1	ENST00000625672.2	TSL:1	c.3341-99797A>C		intron	N/A	ENSP00000485887.1

Frequencies

GnomAD3 genomes AF: 0.366 AC: 55628 AN: 151928 Hom.: 13526 Cov.: 32

Gnomad AFR AF: 0.685

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.323

Gnomad ASJ AF: 0.245

Gnomad EAS AF: 0.493

Gnomad SAS AF: 0.318

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.216

Gnomad OTH AF: 0.340

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

GnomAD4 genome AF: 0.367 AC: 55736 AN: 152046 Hom.: 13570 Cov.: 32 AF XY: 0.363 AC XY: 26997 AN XY: 74332

African (AFR) AF: 0.685 AC: 28390 AN: 41438

American (AMR) AF: 0.323 AC: 4933 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 851 AN: 3472

East Asian (EAS) AF: 0.493 AC: 2544 AN: 5164

South Asian (SAS) AF: 0.319 AC: 1532 AN: 4804

European-Finnish (FIN) AF: 0.175 AC: 1857 AN: 10596

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.216 AC: 14677 AN: 67982

Other (OTH) AF: 0.340 AC: 716 AN: 2108

Alfa AF: 0.272 Hom.: 21796

Bravo AF: 0.399

Asia WGS AF: 0.422 AC: 1470 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.0
DANN	Benign	0.70
PhyloP100		-0.97
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: rs9309181; hg19: chr2-50563905;