rs766942777

Positions:

chr2-50346909-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001330092.2(NRXN1):c.41C>T(p.Ser14Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000384 in 1,295,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00040 ( 0 hom. )

Consequence

NRXN1
NM_001330092.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 3.29

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:

NRXN1 (HGNC:):

NRXN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005674839).

BP6

Variant 2-50346909-G-A is Benign according to our data. Variant chr2-50346909-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 206264.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000258 (39/151024) while in subpopulation SAS AF= 0.000624 (3/4808). AF 95% confidence interval is 0.000306. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRXN1	NM_001330078.2 linkuse as main transcript	c.3365-109939C>T		intron_variant		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.3365-109939C>T		intron_variant		5	NM_001330078.2	ENSP00000385017.2		E7ERL8

Frequencies

GnomAD3 genomes

AF:

0.000258

AC:

AN:

150916

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000661

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000623

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000429

Gnomad OTH

AF:

0.000482

GnomAD3 exomes

AF:

0.000627

AC:

AN:

30310

Hom.:

AF XY:

0.000489

AC XY:

AN XY:

18396

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000459

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00116

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000973

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000401

AC:

459

AN:

1144260

Hom.:

Cov.:

AF XY:

0.000398

AC XY:

221

AN XY:

555956

show subpopulations

Gnomad4 AFR exome

AF:

0.0000434

Gnomad4 AMR exome

AF:

0.0000954

Gnomad4 ASJ exome

AF:

0.0000651

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000904

Gnomad4 FIN exome

AF:

0.0000316

Gnomad4 NFE exome

AF:

0.000408

Gnomad4 OTH exome

AF:

0.000531

GnomAD4 genome

AF:

0.000258

AC:

AN:

151024

Hom.:

Cov.:

AF XY:

0.000285

AC XY:

AN XY:

73774

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.0000660

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000624

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000429

Gnomad4 OTH

AF:

0.000477

Alfa

AF:

0.000356

Hom.:

Bravo

AF:

0.000317

ExAC

AF:

0.000515

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	NRXN1: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 2020	In silico analysis supports that this missense variant does not alter protein structure/function; Missense variant in a gene in which most reported pathogenic variants are truncating/loss-of-function; This variant is in the shorter transcript of NRXN1 (NM_138735.2), and alters a residue that is predicted to be in the signal peptide of the beta-neurexin protein (Zweier et al., 2009); This variant is associated with the following publications: (PMID: 18179900, 24832020, 21424692, 22504536, 17034946, 28289584, 29221905, 18728070) -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2017

The p.S14L variant (also known as c.41C>T), located in coding exon 1 of the NRXN1 gene, results from a C to T substitution at nucleotide position 41. The serine at codon 14 is replaced by leucine, an amino acid with dissimilar properties. In four separate studies, this alteration was detected in 5/944 individuals with ASD, ID, seizures, schizophrenia, and/or non syndromic ID; however, the phenotype of these individuals was variable. In addition, this alteration has been detected in 1/1330 controls (Camacho-Garcia RJ et al. Neurobiol. Dis., 2012 Jul;47:135-43; Yangngam S et al. Genet Test Mol Biomarkers, 2014 Jul;18:510-5; Gauthier J et al. Hum. Genet., 2011 Oct;130:563-73; Feng J et al. Neurosci. Lett., 2006 Nov;409:10-3). In one functional study, authors claimed that cell surface trafficking in COS cells containing this variant was not significantly different than cells containing wild type protein; however, details regarding this data were not provided (Gauthier J et al. Hum. Genet., 2011 Oct;130:563-73). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Pitt-Hopkins-like syndrome 2;C3808494:Chromosome 2p16.3 deletion syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Pitt-Hopkins-like syndrome 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

.;T;.

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.34

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.83

T;T;T

MetaRNN

Benign

0.0057

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.34

N;N;.

PROVEAN

Benign

-1.7

N;.;.

REVEL

Benign

0.068

Sift

Pathogenic

0.0

D;.;.

Sift4G

Benign

0.11

T;T;T

Polyphen

0.0

.;B;.

Vest4

0.28

MutPred

0.28

Loss of glycosylation at S14 (P = 0.0048);Loss of glycosylation at S14 (P = 0.0048);Loss of glycosylation at S14 (P = 0.0048);

MVP

0.043

ClinPred

0.19

GERP RS

3.0

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