rs201802152

chr2-50621200-T-Achr2-50621200-T-Cchr2-50621200-T-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1

The ENST00000404971.5(NRXN1):c.1278+5A>T variant causes a splice donor 5th base, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000915 in 1,554,320 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00074 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00093 ( 4 hom. )

Consequence

NRXN1
ENST00000404971.5 splice_donor_5th_base, intron

Scores

Splicing: ADA: 0.001757

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:9

Conservation

PhyloP100: 8.01

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 2-50621200-T-A is Benign according to our data. Variant chr2-50621200-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129818.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=5, Benign=1}. Variant chr2-50621200-T-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000736 (112/152216) while in subpopulation SAS AF= 0.0029 (14/4828). AF 95% confidence interval is 0.00175. There are 0 homozygotes in gnomad4. There are 66 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 linkuse as main transcript	c.1158+26A>T		intron_variant		ENST00000401669.7
LOC101927089	XR_245002.5 linkuse as main transcript	n.88+189T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRXN1	ENST00000401669.7 linkuse as main transcript	c.1158+26A>T		intron_variant		5	NM_001330078.2	A1
	ENST00000634985.1 linkuse as main transcript	n.49+189T>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000736

AC:

112

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00207

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000970

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00112

AC:

195

AN:

173744

Hom.:

AF XY:

0.00137

AC XY:

125

AN XY:

91416

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000276

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00367

Gnomad FIN exome

AF:

0.00129

Gnomad NFE exome

AF:

0.00108

Gnomad OTH exome

AF:

0.000854

GnomAD4 exome

AF:

0.000934

AC:

1310

AN:

1402104

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

731

AN XY:

692540

show subpopulations

Gnomad4 AFR exome

AF:

0.0000625

Gnomad4 AMR exome

AF:

0.000275

Gnomad4 ASJ exome

AF:

0.0000399

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00423

Gnomad4 FIN exome

AF:

0.00131

Gnomad4 NFE exome

AF:

0.000756

Gnomad4 OTH exome

AF:

0.00105

GnomAD4 genome

AF:

0.000736

AC:

112

AN:

152216

Hom.:

Cov.:

AF XY:

0.000887

AC XY:

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.00207

Gnomad4 NFE

AF:

0.000970

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000751

Hom.:

Bravo

AF:

0.000616

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 28, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	NRXN1: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 04, 2020	Has not been previously published as pathogenic or benign to our knowledge -

Pitt-Hopkins-like syndrome 2

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 23, 2020

The c.1278+5A>T intronic alteration consists of an A to T substitution 5 nucleotides after exon 8 (coding exon 7) in the NRXN1 gene. Based on data from the Genome Aggregation Database (gnomAD) database, the NRXN1 c.1278+5A>T alteration was observed in 0.1% (207/205140) of total alleles studied, with a frequency of 0.37% (84/22894) in the South Asian subpopulation. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Intellectual disability

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

not specified

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 12, 2018

- -

NRXN1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 07, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

Cadd

Benign

Dann

Benign

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0018

dbscSNV1_RF

Benign

0.14

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