rs1553368900

Variant names:

• chr2-50925809-ACACAATCCAGAAACCAACAAATGTTCAGAAAGAAGTTCAACTTACCATCTAACTTCAAGATGTACCCTATTAGTACTAAGAAATAAAGGACAAATGAGAGTTGGAAAAATAAGGTAGAAAGCACCCACCTTCCACATTGTTGTCTTCTGAAAGCACATGACAAGGAGGGAGAGAAAAGGAAAAACATTCATTAAGCAGCATGCAGACTGGACCTTGCCTTTGCATGTCTTCCTCATGCAAGGCACCAAACACATCATGCAAGTGCTCCATCACTATCATTCAAGGGGGAAAACAAAATCACAGGGAAGCAGGTTCCCTCCCATTGGCAGCATTGATAGGAAGTGAGACAAACTTTCATAATACTGCCATGCCCTGTGCAAAGAGTTTTTAAAAAAATCTTTCAACTACCCAGTATAAAGCAAACATTATTGTTATTACATGTTGCTGGTG-A
• rs1553368900
• NM_001330078.2:c.773-304_790+128del

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PP5_Moderate

The NM_001330078.2(NRXN1):​c.773-304_790+128del variant causes a exon loss, splice acceptor, splice donor, splice region, intron change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NRXN1 NM_001330078.2 exon_loss, splice_acceptor, splice_donor, splice_region, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.97
• Publications: 0 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: 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: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.00397878 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP5: Variant 2-50925809-ACACAATCCAGAAACCAACAAATGTTCAGAAAGAAGTTCAACTTACCATCTAACTTCAAGATGTACCCTATTAGTACTAAGAAATAAAGGACAAATGAGAGTTGGAAAAATAAGGTAGAAAGCACCCACCTTCCACATTGTTGTCTTCTGAAAGCACATGACAAGGAGGGAGAGAAAAGGAAAAACATTCATTAAGCAGCATGCAGACTGGACCTTGCCTTTGCATGTCTTCCTCATGCAAGGCACCAAACACATCATGCAAGTGCTCCATCACTATCATTCAAGGGGGAAAACAAAATCACAGGGAAGCAGGTTCCCTCCCATTGGCAGCATTGATAGGAAGTGAGACAAACTTTCATAATACTGCCATGCCCTGTGCAAAGAGTTTTTAAAAAAATCTTTCAACTACCCAGTATAAAGCAAACATTATTGTTATTACATGTTGCTGGTG-A is Pathogenic according to our data. Variant chr2-50925809-ACACAATCCAGAAACCAACAAATGTTCAGAAAGAAGTTCAACTTACCATCTAACTTCAAGATGTACCCTATTAGTACTAAGAAATAAAGGACAAATGAGAGTTGGAAAAATAAGGTAGAAAGCACCCACCTTCCACATTGTTGTCTTCTGAAAGCACATGACAAGGAGGGAGAGAAAAGGAAAAACATTCATTAAGCAGCATGCAGACTGGACCTTGCCTTTGCATGTCTTCCTCATGCAAGGCACCAAACACATCATGCAAGTGCTCCATCACTATCATTCAAGGGGGAAAACAAAATCACAGGGAAGCAGGTTCCCTCCCATTGGCAGCATTGATAGGAAGTGAGACAAACTTTCATAATACTGCCATGCCCTGTGCAAAGAGTTTTTAAAAAAATCTTTCAACTACCCAGTATAAAGCAAACATTATTGTTATTACATGTTGCTGGTG-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 560109.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN1	NM_001330078.2	MANE Select	c.773-304_790+128del		exon_loss splice_acceptor splice_donor splice_region intron	Exon 3 of 23	NP_001317007.1	Q9ULB1-5
	NRXN1	NM_001135659.3		c.872-304_889+128del		exon_loss splice_acceptor splice_donor splice_region intron	Exon 4 of 24	NP_001129131.1	Q9ULB1-3
	NRXN1	NM_001330093.2		c.773-307_787+128del		exon_loss splice_acceptor splice_donor splice_region intron	Exon 3 of 23	NP_001317022.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN1	ENST00000401669.7	TSL:5 MANE Select	c.773-304_790+128del		exon_loss splice_acceptor splice_donor splice_region intron	Exon 3 of 23	ENSP00000385017.2	Q9ULB1-5
	NRXN1	ENST00000404971.5	TSL:1	c.872-304_889+128del		exon_loss splice_acceptor splice_donor splice_region intron	Exon 4 of 24	ENSP00000385142.1	Q9ULB1-3
	NRXN1	ENST00000625672.2	TSL:1	c.773-304_790+128del		exon_loss splice_acceptor splice_donor splice_region intron	Exon 2 of 21	ENSP00000485887.1	Q9ULB1-2

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.0

Splicing

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

Other links and lift over

dbSNP: rs1553368900; hg19: chr2-51152947;