2-51036011-A-G

Variant names:

• chr2-51036011-A-G
• rs1995584
• ENST00000440698.1:n.416+2995A>G

Variant summary

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

The ENST00000440698.1(NRXN1-DT):​n.416+2995A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.602 in 151,894 control chromosomes in the GnomAD database, including 27,827 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 0.60 (27827 hom., cov: 31)
• Consequence: NRXN1-DT ENST00000440698.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.308
• Publications: 5 publications found

Genes affected

NRXN1-DT (HGNC:52686): (NRXN1 divergent transcript)

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 (AFR) allele frequency at 95% confidence interval = 0.694 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000440698.1. 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-DT	NR_135237.1		n.416+2995A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN1-DT	ENST00000440698.1	TSL:2	n.416+2995A>G		intron	N/A
	NRXN1	ENST00000635126.1	TSL:5	n.320-2877T>C		intron	N/A
	NRXN1	ENST00000635310.1	TSL:5	n.426-6817T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.602 AC: 91346 AN: 151776 Hom.: 27790 Cov.: 31

Gnomad AFR AF: 0.700

Gnomad AMI AF: 0.595

Gnomad AMR AF: 0.549

Gnomad ASJ AF: 0.586

Gnomad EAS AF: 0.563

Gnomad SAS AF: 0.665

Gnomad FIN AF: 0.535

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.565

Gnomad OTH AF: 0.562

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

GnomAD4 genome AF: 0.602 AC: 91440 AN: 151894 Hom.: 27827 Cov.: 31 AF XY: 0.601 AC XY: 44569 AN XY: 74214

African (AFR) AF: 0.700 AC: 29019 AN: 41434

American (AMR) AF: 0.549 AC: 8373 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.586 AC: 2036 AN: 3472

East Asian (EAS) AF: 0.562 AC: 2891 AN: 5148

South Asian (SAS) AF: 0.664 AC: 3200 AN: 4816

European-Finnish (FIN) AF: 0.535 AC: 5635 AN: 10534

Middle Eastern (MID) AF: 0.636 AC: 187 AN: 294

European-Non Finnish (NFE) AF: 0.565 AC: 38367 AN: 67928

Other (OTH) AF: 0.564 AC: 1189 AN: 2108

Alfa AF: 0.562 Hom.: 12349

Bravo AF: 0.601

Asia WGS AF: 0.617 AC: 2141 AN: 3472

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	0.86
PhyloP100		0.31

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1995584; hg19: chr2-51263149;