2-51040002-C-T

Variant names:

• chr2-51040002-C-T
• rs2193411
• ENST00000440698.1:n.416+6986C>T

Variant summary

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

The ENST00000440698.1(NRXN1-DT):​n.416+6986C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 152,092 control chromosomes in the GnomAD database, including 2,549 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 0.15 (2549 hom., cov: 33)
• Consequence: NRXN1-DT ENST00000440698.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.56
• Publications: 0 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: Ambry Genetics, G2P, 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.304 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN1-DT	NR_135237.1		n.416+6986C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN1-DT	ENST00000440698.1	TSL:2	n.416+6986C>T		intron	N/A
	NRXN1	ENST00000635126.1	TSL:5	n.320-6868G>A		intron	N/A
	NRXN1	ENST00000635310.1	TSL:5	n.426-10808G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23065 AN: 151974 Hom.: 2539 Cov.: 33

Gnomad AFR AF: 0.309

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.0904

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.0695

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.0852

Gnomad OTH AF: 0.156

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

GnomAD4 genome AF: 0.152 AC: 23105 AN: 152092 Hom.: 2549 Cov.: 33 AF XY: 0.150 AC XY: 11160 AN XY: 74350

African (AFR) AF: 0.309 AC: 12802 AN: 41446

American (AMR) AF: 0.0903 AC: 1380 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 461 AN: 3466

East Asian (EAS) AF: 0.120 AC: 618 AN: 5162

South Asian (SAS) AF: 0.175 AC: 843 AN: 4814

European-Finnish (FIN) AF: 0.0695 AC: 737 AN: 10604

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.0852 AC: 5795 AN: 67996

Other (OTH) AF: 0.159 AC: 337 AN: 2116

Alfa AF: 0.111 Hom.: 2810

Bravo AF: 0.160

Asia WGS AF: 0.169 AC: 586 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.55
DANN	Benign	0.31
PhyloP100		-2.6

Splicing

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

Other links and lift over

dbSNP: rs2193411; hg19: chr2-51267140;