2-49921834-C-A

Variant names:

• chr2-49921834-C-A
• rs1045881
• NM_001330078.2:c.*110G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001330078.2(NRXN1):​c.*110G>T variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.00000111 in 904,040 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: NRXN1 NM_001330078.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.22
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.19).

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.*110G>T		3_prime_UTR	Exon 23 of 23	NP_001317007.1	Q9ULB1-5
	NRXN1	NM_001135659.3		c.*110G>T		3_prime_UTR	Exon 24 of 24	NP_001129131.1	Q9ULB1-3
	NRXN1	NM_001330093.2		c.*110G>T		3_prime_UTR	Exon 23 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.*110G>T		3_prime_UTR	Exon 23 of 23	ENSP00000385017.2	Q9ULB1-5
	NRXN1	ENST00000404971.5	TSL:1	c.*110G>T		3_prime_UTR	Exon 24 of 24	ENSP00000385142.1	Q9ULB1-3
	NRXN1	ENST00000625672.2	TSL:1	c.*110G>T		3_prime_UTR	Exon 21 of 21	ENSP00000485887.1	Q9ULB1-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000111 AC: 1 AN: 904040 Hom.: 0 Cov.: 12 AF XY: 0.00000218 AC XY: 1 AN XY: 458832

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 20712

American (AMR) AF: 0.00 AC: 0 AN: 24966

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18730

East Asian (EAS) AF: 0.00 AC: 0 AN: 34312

South Asian (SAS) AF: 0.00 AC: 0 AN: 58522

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44882

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3122

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 658334

Other (OTH) AF: 0.0000247 AC: 1 AN: 40460

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.19
CADD	Benign	18
DANN	Benign	0.91
PhyloP100		4.2

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: rs1045881; hg19: chr2-50148972;