rs1045881

Positions:

• chr2-49921834-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001330078.2(NRXN1):​c.*110G>A variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.165 in 1,054,496 control chromosomes in the GnomAD database, including 15,741 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1882 hom., cov: 32)
  • Exomes 𝑓: 0.17 (13859 hom.)
• Consequence: NRXN1 NM_001330078.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.22

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.2).
• BP6: Variant 2-49921834-C-T is Benign according to our data. Variant chr2-49921834-C-T is described in ClinVar as [Benign]. Clinvar id is 336539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRXN1	NM_001330078.2	c.*110G>A		3_prime_UTR_variant	23/23	ENST00000401669.7	NP_001317007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRXN1	ENST00000401669.7	c.*110G>A		3_prime_UTR_variant	23/23	5	NM_001330078.2	ENSP00000385017	A1

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23223 AN: 151810 Hom.: 1883 Cov.: 32

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.213

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.310

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.159

GnomAD4 exome AF: 0.167 AC: 150826 AN: 902568 Hom.: 13859 Cov.: 12 AF XY: 0.173 AC XY: 79274 AN XY: 458056

Gnomad4 AFR exome AF: 0.128

Gnomad4 AMR exome AF: 0.0915

Gnomad4 ASJ exome AF: 0.163

Gnomad4 EAS exome AF: 0.135

Gnomad4 SAS exome AF: 0.313

Gnomad4 FIN exome AF: 0.149

Gnomad4 NFE exome AF: 0.161

Gnomad4 OTH exome AF: 0.171

GnomAD4 genome AF: 0.153 AC: 23224 AN: 151928 Hom.: 1882 Cov.: 32 AF XY: 0.155 AC XY: 11477 AN XY: 74268

Gnomad4 AFR AF: 0.131

Gnomad4 AMR AF: 0.117

Gnomad4 ASJ AF: 0.167

Gnomad4 EAS AF: 0.144

Gnomad4 SAS AF: 0.311

Gnomad4 FIN AF: 0.161

Gnomad4 NFE AF: 0.161

Gnomad4 OTH AF: 0.156

Alfa AF: 0.166 Hom.: 4650

Bravo AF: 0.146

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2018	This variant is associated with the following publications: (PMID: 21687627) -

Pitt-Hopkins-like syndrome 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.20
CADD	Benign	18
DANN	Benign	0.91

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

Publications

LitVar

Other links and lift over

dbSNP: rs1045881; hg19: chr2-50148972; COSMIC: COSV60489450; COSMIC: COSV60489450;