rs1045874

Variant names:

• chr2-51027763-G-A
• rs1045874
• NM_001330078.2:c.511C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-51027763-G-A
• chr2-51027763-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001330078.2(NRXN1):​c.511C>T​(p.Leu171Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0978 in 1,611,952 control chromosomes in the GnomAD database, including 13,137 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (4220 hom., cov: 33)
  • Exomes 𝑓: 0.089 (8917 hom.)
• Consequence: NRXN1 NM_001330078.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.80
• Publications: 13 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: G2P, Ambry Genetics, 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 2-51027763-G-A is Benign according to our data. Variant chr2-51027763-G-A is described in ClinVar as Benign. ClinVar VariationId is 93603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.8 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRXN1	NM_001330078.2	c.511C>T	p.Leu171Leu	synonymous_variant	Exon 2 of 23	ENST00000401669.7	NP_001317007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRXN1	ENST00000401669.7	c.511C>T	p.Leu171Leu	synonymous_variant	Exon 2 of 23	5	NM_001330078.2	ENSP00000385017.2

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27078 AN: 152046 Hom.: 4205 Cov.: 33

Gnomad AFR AF: 0.422

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.0976

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.0679

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.0750

Gnomad OTH AF: 0.174

GnomAD2 exomes AF: 0.113 AC: 27624 AN: 243570 AF XY: 0.113

Gnomad AFR exome AF: 0.436

Gnomad AMR exome AF: 0.0660

Gnomad ASJ exome AF: 0.123

Gnomad EAS exome AF: 0.132

Gnomad FIN exome AF: 0.0677

Gnomad NFE exome AF: 0.0752

Gnomad OTH exome AF: 0.103

GnomAD4 exome AF: 0.0894 AC: 130504 AN: 1459788 Hom.: 8917 Cov.: 32 AF XY: 0.0913 AC XY: 66298 AN XY: 726114

African (AFR) AF: 0.448 AC: 14984 AN: 33412

American (AMR) AF: 0.0707 AC: 3149 AN: 44522

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 3217 AN: 26048

East Asian (EAS) AF: 0.106 AC: 4213 AN: 39624

South Asian (SAS) AF: 0.169 AC: 14531 AN: 85976

European-Finnish (FIN) AF: 0.0688 AC: 3651 AN: 53052

Middle Eastern (MID) AF: 0.157 AC: 906 AN: 5766

European-Non Finnish (NFE) AF: 0.0712 AC: 79094 AN: 1111086

Other (OTH) AF: 0.112 AC: 6759 AN: 60302

GnomAD4 genome AF: 0.178 AC: 27136 AN: 152164 Hom.: 4220 Cov.: 33 AF XY: 0.177 AC XY: 13131 AN XY: 74386

African (AFR) AF: 0.422 AC: 17495 AN: 41480

American (AMR) AF: 0.0975 AC: 1492 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 401 AN: 3472

East Asian (EAS) AF: 0.120 AC: 615 AN: 5126

South Asian (SAS) AF: 0.167 AC: 803 AN: 4822

European-Finnish (FIN) AF: 0.0679 AC: 721 AN: 10624

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.0750 AC: 5103 AN: 68008

Other (OTH) AF: 0.177 AC: 375 AN: 2116

Alfa AF: 0.107 Hom.: 756

Bravo AF: 0.192

Asia WGS AF: 0.172 AC: 600 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Pitt-Hopkins-like syndrome 2 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Jan 08, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.51
CADD	Benign	7.7
DANN	Benign	0.91
PhyloP100		2.8
PromoterAI		-0.014	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs1045874; hg19: chr2-51254901; COSMIC: COSV68016073; COSMIC: COSV68016073;