rs1045874

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.80

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 93603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-51027763-G-A is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
NRXN1	NM_001330078.2 linkuse as main transcript	c.511C>T	p.Leu171Leu	synonymous_variant	2/23	ENST00000401669.7	NP_001317007.1	E7ERL8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRXN1	ENST00000401669.7 linkuse as main transcript	c.511C>T	p.Leu171Leu	synonymous_variant	2/23	5	NM_001330078.2	ENSP00000385017.2		E7ERL8

Frequencies

GnomAD3 genomes

AF:

0.178

AC:

27078

AN:

152046

Hom.:

4205

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.113

AC:

27624

AN:

243570

Hom.:

2588

AF XY:

0.113

AC XY:

15067

AN XY:

132822

show subpopulations

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 SAS exome

AF:

0.169

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.:

AF XY:

0.0913

AC XY:

66298

AN XY:

726114

show subpopulations

Gnomad4 AFR exome

AF:

0.448

Gnomad4 AMR exome

AF:

0.0707

Gnomad4 ASJ exome

AF:

0.124

Gnomad4 EAS exome

AF:

0.106

Gnomad4 SAS exome

AF:

0.169

Gnomad4 FIN exome

AF:

0.0688

Gnomad4 NFE exome

AF:

0.0712

Gnomad4 OTH exome

AF:

0.112

GnomAD4 genome

AF:

0.178

AC:

27136

AN:

152164

Hom.:

4220

Cov.:

AF XY:

0.177

AC XY:

13131

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.422

Gnomad4 AMR

AF:

0.0975

Gnomad4 ASJ

AF:

0.115

Gnomad4 EAS

AF:

0.120

Gnomad4 SAS

AF:

0.167

Gnomad4 FIN

AF:

0.0679

Gnomad4 NFE

AF:

0.0750

Gnomad4 OTH

AF:

0.177

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

LINK: link

Submissions by phenotype

not specified

Benign:3

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, 2015	- -
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. -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 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

-0.51

CADD

Benign

7.7

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over