2-50441622-T-C

Variant names:

• chr2-50441622-T-C
• rs10048731
• NM_001330078.2:c.3364+23820A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001330078.2(NRXN1):​c.3364+23820A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.313 in 152,012 control chromosomes in the GnomAD database, including 7,865 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 (7865 hom., cov: 32)
• Consequence: NRXN1 NM_001330078.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0770
• Publications: 3 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.452 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.3364+23820A>G		intron	N/A	NP_001317007.1
	NRXN1	NM_001135659.3		c.3484+23820A>G		intron	N/A	NP_001129131.1
	NRXN1	NM_001330093.2		c.3361+23820A>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.3364+23820A>G		intron	N/A	ENSP00000385017.2
	NRXN1	ENST00000404971.5	TSL:1	c.3484+23820A>G		intron	N/A	ENSP00000385142.1
	NRXN1	ENST00000625672.2	TSL:1	c.3340+23820A>G		intron	N/A	ENSP00000485887.1

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47495 AN: 151894 Hom.: 7846 Cov.: 32

Gnomad AFR AF: 0.380

Gnomad AMI AF: 0.201

Gnomad AMR AF: 0.312

Gnomad ASJ AF: 0.203

Gnomad EAS AF: 0.467

Gnomad SAS AF: 0.361

Gnomad FIN AF: 0.313

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.305

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

GnomAD4 genome AF: 0.313 AC: 47556 AN: 152012 Hom.: 7865 Cov.: 32 AF XY: 0.316 AC XY: 23473 AN XY: 74296

African (AFR) AF: 0.380 AC: 15758 AN: 41484

American (AMR) AF: 0.313 AC: 4770 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 705 AN: 3470

East Asian (EAS) AF: 0.467 AC: 2408 AN: 5152

South Asian (SAS) AF: 0.360 AC: 1738 AN: 4822

European-Finnish (FIN) AF: 0.313 AC: 3297 AN: 10550

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.264 AC: 17959 AN: 67956

Other (OTH) AF: 0.310 AC: 654 AN: 2110

Alfa AF: 0.280 Hom.: 26298

Bravo AF: 0.314

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	11
DANN	Benign	0.82
PhyloP100		0.077
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: rs10048731; hg19: chr2-50668760;