rs2303298

Positions:

chr2-50623548-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001330078.2(NRXN1):c.900C>T(p.Pro300=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,613,166 control chromosomes in the GnomAD database, including 931 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 91 hom., cov: 32)

Exomes 𝑓: 0.011 ( 840 hom. )

Consequence

NRXN1
NM_001330078.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.729

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 2-50623548-G-A is Benign according to our data. Variant chr2-50623548-G-A is described in ClinVar as [Benign]. Clinvar id is 129827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.729 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.103 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.900C>T	p.Pro300=	synonymous_variant	6/23	ENST00000401669.7	NP_001317007.1
LOC101927089	XR_245002.5 linkuse as main transcript	n.89-1263G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRXN1	ENST00000401669.7 linkuse as main transcript	c.900C>T	p.Pro300=	synonymous_variant	6/23	5	NM_001330078.2	ENSP00000385017	A1
	ENST00000634985.1 linkuse as main transcript	n.50-1263G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0197

AC:

2999

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0348

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0409

Gnomad ASJ

AF:

0.00721

Gnomad EAS

AF:

0.110

Gnomad SAS

AF:

0.0139

Gnomad FIN

AF:

0.00622

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00244

Gnomad OTH

AF:

0.0177

GnomAD3 exomes

AF:

0.0251

AC:

6249

AN:

248600

Hom.:

248

AF XY:

0.0219

AC XY:

2955

AN XY:

134818

show subpopulations

Gnomad AFR exome

AF:

0.0363

Gnomad AMR exome

AF:

0.0837

Gnomad ASJ exome

AF:

0.00826

Gnomad EAS exome

AF:

0.101

Gnomad SAS exome

AF:

0.0101

Gnomad FIN exome

AF:

0.00743

Gnomad NFE exome

AF:

0.00286

Gnomad OTH exome

AF:

0.0192

GnomAD4 exome

AF:

0.0110

AC:

16110

AN:

1460964

Hom.:

840

Cov.:

AF XY:

0.0107

AC XY:

7769

AN XY:

726798

show subpopulations

Gnomad4 AFR exome

AF:

0.0398

Gnomad4 AMR exome

AF:

0.0788

Gnomad4 ASJ exome

AF:

0.00766

Gnomad4 EAS exome

AF:

0.161

Gnomad4 SAS exome

AF:

0.0104

Gnomad4 FIN exome

AF:

0.00787

Gnomad4 NFE exome

AF:

0.00229

Gnomad4 OTH exome

AF:

0.0123

GnomAD4 genome

AF:

0.0198

AC:

3013

AN:

152202

Hom.:

Cov.:

AF XY:

0.0211

AC XY:

1569

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.0351

Gnomad4 AMR

AF:

0.0410

Gnomad4 ASJ

AF:

0.00721

Gnomad4 EAS

AF:

0.110

Gnomad4 SAS

AF:

0.0131

Gnomad4 FIN

AF:

0.00622

Gnomad4 NFE

AF:

0.00244

Gnomad4 OTH

AF:

0.0170

Alfa

AF:

0.00893

Hom.:

Bravo

AF:

0.0250

Asia WGS

AF:

0.0520

AC:

180

AN:

3478

EpiCase

AF:

0.00235

EpiControl

AF:

0.00314

ClinVar

Significance: Benign

Submissions summary: Benign:9

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	-	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 03, 2014	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 28, 2018	- -

Pitt-Hopkins-like syndrome 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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. -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 14, 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

-0.46

CADD

Benign

9.1

DANN

Benign

0.65

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