rs2303298

chr2-50623548-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001330078.2(NRXN1):c.900C>T(p.Pro300=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,613,166 control chromosomes in the GnomAD database, including 931 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (91 hom., cov: 32)
  • Exomes 𝑓: 0.011 (840 hom.)
• Consequence: NRXN1 NM_001330078.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.729

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 2-50623548-G-A is Benign according to our data. Variant chr2-50623548-G-A is described in ClinVar as [Benign]. Clinvar id is 129827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.729 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRXN1	NM_001330078.2	c.900C>T	p.Pro300=	synonymous_variant	6/23	ENST00000401669.7
LOC101927089	XR_245002.5	n.89-1263G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRXN1	ENST00000401669.7	c.900C>T	p.Pro300=	synonymous_variant	6/23	5	NM_001330078.2	A1
	ENST00000634985.1	n.50-1263G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0197 AC: 2999 AN: 152084 Hom.: 89 Cov.: 32

Gnomad AFR AF: 0.0348

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0409

Gnomad ASJ AF: 0.00721

Gnomad EAS AF: 0.110

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.00622

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00244

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.0251 AC: 6249 AN: 248600 Hom.: 248 AF XY: 0.0219 AC XY: 2955 AN XY: 134818

Gnomad AFR exome AF: 0.0363

Gnomad AMR exome AF: 0.0837

Gnomad ASJ exome AF: 0.00826

Gnomad EAS exome AF: 0.101

Gnomad SAS exome AF: 0.0101

Gnomad FIN exome AF: 0.00743

Gnomad NFE exome AF: 0.00286

Gnomad OTH exome AF: 0.0192

GnomAD4 exome AF: 0.0110 AC: 16110 AN: 1460964 Hom.: 840 Cov.: 31 AF XY: 0.0107 AC XY: 7769 AN XY: 726798

Gnomad4 AFR exome AF: 0.0398

Gnomad4 AMR exome AF: 0.0788

Gnomad4 ASJ exome AF: 0.00766

Gnomad4 EAS exome AF: 0.161

Gnomad4 SAS exome AF: 0.0104

Gnomad4 FIN exome AF: 0.00787

Gnomad4 NFE exome AF: 0.00229

Gnomad4 OTH exome AF: 0.0123

GnomAD4 genome AF: 0.0198 AC: 3013 AN: 152202 Hom.: 91 Cov.: 32 AF XY: 0.0211 AC XY: 1569 AN XY: 74436

Gnomad4 AFR AF: 0.0351

Gnomad4 AMR AF: 0.0410

Gnomad4 ASJ AF: 0.00721

Gnomad4 EAS AF: 0.110

Gnomad4 SAS AF: 0.0131

Gnomad4 FIN AF: 0.00622

Gnomad4 NFE AF: 0.00244

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.00893 Hom.: 52

Bravo AF: 0.0250

Asia WGS AF: 0.0520 AC: 180 AN: 3478

EpiCase AF: 0.00235

EpiControl AF: 0.00314

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 03, 2014	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 28, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Pitt-Hopkins-like syndrome 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	Invitae	Feb 01, 2024	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 14, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	9.1
Dann	Benign	0.65

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: rs2303298; hg19: chr2-50850686; COSMIC: COSV58442398; COSMIC: COSV58442398;