2-50880995-A-G

Variant names:

• chr2-50880995-A-G
• rs983936
• NM_001330078.2:c.832+40874T>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.832+40874T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.529 in 151,836 control chromosomes in the GnomAD database, including 23,178 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 0.53 (23178 hom., cov: 32)
• Consequence: NRXN1 NM_001330078.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.58
• Publications: 4 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=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.66 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.832+40874T>C		intron	N/A	NP_001317007.1
	NRXN1	NM_001135659.3		c.931+40874T>C		intron	N/A	NP_001129131.1
	NRXN1	NM_001330093.2		c.829+40874T>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.832+40874T>C		intron	N/A	ENSP00000385017.2
	NRXN1	ENST00000404971.5	TSL:1	c.931+40874T>C		intron	N/A	ENSP00000385142.1
	NRXN1	ENST00000625672.2	TSL:1	c.832+40874T>C		intron	N/A	ENSP00000485887.1

Frequencies

GnomAD3 genomes AF: 0.529 AC: 80315 AN: 151718 Hom.: 23186 Cov.: 32

Gnomad AFR AF: 0.316

Gnomad AMI AF: 0.530

Gnomad AMR AF: 0.485

Gnomad ASJ AF: 0.644

Gnomad EAS AF: 0.278

Gnomad SAS AF: 0.461

Gnomad FIN AF: 0.668

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.665

Gnomad OTH AF: 0.525

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

GnomAD4 genome AF: 0.529 AC: 80322 AN: 151836 Hom.: 23178 Cov.: 32 AF XY: 0.525 AC XY: 38952 AN XY: 74202

African (AFR) AF: 0.316 AC: 13079 AN: 41436

American (AMR) AF: 0.485 AC: 7382 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.644 AC: 2230 AN: 3464

East Asian (EAS) AF: 0.277 AC: 1418 AN: 5122

South Asian (SAS) AF: 0.462 AC: 2228 AN: 4826

European-Finnish (FIN) AF: 0.668 AC: 7069 AN: 10580

Middle Eastern (MID) AF: 0.612 AC: 180 AN: 294

European-Non Finnish (NFE) AF: 0.665 AC: 45143 AN: 67854

Other (OTH) AF: 0.525 AC: 1110 AN: 2114

Alfa AF: 0.612 Hom.: 92970

Bravo AF: 0.503

Asia WGS AF: 0.380 AC: 1321 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.10
DANN	Benign	0.32
PhyloP100		-1.6
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: rs983936; hg19: chr2-51108133;