chr2-50021775-A-G

Variant names:

• chr2-50021775-A-G
• rs10495995
• NM_001330078.2:c.4128+31496T>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.4128+31496T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.722 in 152,076 control chromosomes in the GnomAD database, including 39,912 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 0.72 (39912 hom., cov: 32)
• Consequence: NRXN1 NM_001330078.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.101
• Publications: 1 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.772 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+31496T>C		intron	N/A	NP_001317007.1
	NRXN1	NM_001135659.3		c.4248+31496T>C		intron	N/A	NP_001129131.1
	NRXN1	NM_001330093.2		c.4125+31496T>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.4128+31496T>C		intron	N/A	ENSP00000385017.2
	NRXN1	ENST00000404971.5	TSL:1	c.4248+31496T>C		intron	N/A	ENSP00000385142.1
	NRXN1	ENST00000625672.2	TSL:1	c.4104+31496T>C		intron	N/A	ENSP00000485887.1

Frequencies

GnomAD3 genomes AF: 0.722 AC: 109778 AN: 151958 Hom.: 39871 Cov.: 32

Gnomad AFR AF: 0.779

Gnomad AMI AF: 0.735

Gnomad AMR AF: 0.672

Gnomad ASJ AF: 0.680

Gnomad EAS AF: 0.677

Gnomad SAS AF: 0.624

Gnomad FIN AF: 0.748

Gnomad MID AF: 0.755

Gnomad NFE AF: 0.708

Gnomad OTH AF: 0.702

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

GnomAD4 genome AF: 0.722 AC: 109863 AN: 152076 Hom.: 39912 Cov.: 32 AF XY: 0.721 AC XY: 53574 AN XY: 74336

African (AFR) AF: 0.779 AC: 32326 AN: 41480

American (AMR) AF: 0.672 AC: 10267 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.680 AC: 2358 AN: 3468

East Asian (EAS) AF: 0.677 AC: 3490 AN: 5156

South Asian (SAS) AF: 0.622 AC: 2994 AN: 4814

European-Finnish (FIN) AF: 0.748 AC: 7910 AN: 10576

Middle Eastern (MID) AF: 0.764 AC: 223 AN: 292

European-Non Finnish (NFE) AF: 0.708 AC: 48155 AN: 67994

Other (OTH) AF: 0.697 AC: 1471 AN: 2110

Alfa AF: 0.730 Hom.: 5261

Bravo AF: 0.717

Asia WGS AF: 0.633 AC: 2201 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.7
DANN	Benign	0.57
PhyloP100		-0.10
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: rs10495995; hg19: chr2-50248913;