2-50222000-C-T

Variant names:

• chr2-50222000-C-T
• rs601010
• NM_001330078.2:c.3546+14789G>A

Variant summary

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

The NM_001135659.3(NRXN1):​c.3666+14789G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.548 in 151,726 control chromosomes in the GnomAD database, including 23,110 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 0.55 (23110 hom., cov: 32)
• Consequence: NRXN1 NM_001135659.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.171
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.59 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001135659.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN1	NM_001330078.2	MANE Select	c.3546+14789G>A		intron	N/A	NP_001317007.1
	NRXN1	NM_001135659.3		c.3666+14789G>A		intron	N/A	NP_001129131.1
	NRXN1	NM_001330093.2		c.3543+14789G>A		intron	N/A	NP_001317022.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN1	ENST00000401669.7	TSL:5 MANE Select	c.3546+14789G>A		intron	N/A	ENSP00000385017.2
	NRXN1	ENST00000404971.5	TSL:1	c.3666+14789G>A		intron	N/A	ENSP00000385142.1
	NRXN1	ENST00000625672.2	TSL:1	c.3522+14789G>A		intron	N/A	ENSP00000485887.1

Frequencies

GnomAD3 genomes AF: 0.548 AC: 83150 AN: 151608 Hom.: 23093 Cov.: 32

Gnomad AFR AF: 0.596

Gnomad AMI AF: 0.541

Gnomad AMR AF: 0.513

Gnomad ASJ AF: 0.448

Gnomad EAS AF: 0.391

Gnomad SAS AF: 0.496

Gnomad FIN AF: 0.629

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.536

Gnomad OTH AF: 0.536

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

GnomAD4 genome AF: 0.548 AC: 83215 AN: 151726 Hom.: 23110 Cov.: 32 AF XY: 0.549 AC XY: 40670 AN XY: 74112

African (AFR) AF: 0.596 AC: 24703 AN: 41434

American (AMR) AF: 0.513 AC: 7786 AN: 15176

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 1552 AN: 3468

East Asian (EAS) AF: 0.392 AC: 2008 AN: 5122

South Asian (SAS) AF: 0.496 AC: 2388 AN: 4814

European-Finnish (FIN) AF: 0.629 AC: 6635 AN: 10556

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.536 AC: 36359 AN: 67840

Other (OTH) AF: 0.534 AC: 1126 AN: 2110

Alfa AF: 0.519 Hom.: 9245

Bravo AF: 0.541

Asia WGS AF: 0.444 AC: 1543 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.39
DANN	Benign	0.66
PhyloP100		-0.17
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: rs601010; hg19: chr2-50449138;