rs766942777

chr2-50346909-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The ENST00000342183.9(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 ENST00000342183.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 3.29

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 -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: {Uncertain_significance=2, Likely_benign=3}.
• 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	UniProt
NRXN1	NM_001330078.2	c.3365-109939C>T		intron_variant		ENST00000401669.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRXN1	ENST00000401669.7	c.3365-109939C>T		intron_variant		5	NM_001330078.2	A1

Frequencies

GnomAD3 genomes AF: 0.000258 AC: 39 AN: 150916 Hom.: 0 Cov.: 32

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: 19 AN: 30310 Hom.: 0 AF XY: 0.000489 AC XY: 9 AN XY: 18396

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.: 0 Cov.: 30 AF XY: 0.000398 AC XY: 221 AN XY: 555956

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: 39 AN: 151024 Hom.: 0 Cov.: 32 AF XY: 0.000285 AC XY: 21 AN XY: 73774

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.: 0

Bravo AF: 0.000317

ExAC AF: 0.000515 AC: 7

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

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) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	NRXN1: BP4 -

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

Invitae

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	18
Dann	Uncertain	0.99
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.83	T;T;T
MetaRNN	Benign	0.0057	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N;N;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;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	T
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

Other links and lift over

dbSNP: rs766942777; hg19: chr2-50574047;