rs200248561

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS1

The NM_001330078.2(NRXN1):ā€‹c.501C>Gā€‹(p.Leu167=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000358 in 1,612,478 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.0014 ( 1 hom., cov: 33)
Exomes š‘“: 0.00025 ( 1 hom. )

Consequence

NRXN1
NM_001330078.2 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.717
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.51).
BP6
Variant 2-51027773-G-C is Benign according to our data. Variant chr2-51027773-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 138557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-51027773-G-C is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=0.717 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00137 (208/152280) while in subpopulation AFR AF= 0.00416 (173/41572). AF 95% confidence interval is 0.00366. There are 1 homozygotes in gnomad4. There are 105 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NRXN1NM_001330078.2 linkuse as main transcriptc.501C>G p.Leu167= synonymous_variant 2/23 ENST00000401669.7 NP_001317007.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NRXN1ENST00000401669.7 linkuse as main transcriptc.501C>G p.Leu167= synonymous_variant 2/235 NM_001330078.2 ENSP00000385017 A1

Frequencies

GnomAD3 genomes
AF:
0.00135
AC:
205
AN:
152160
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00410
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000916
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000220
Gnomad OTH
AF:
0.00239
GnomAD3 exomes
AF:
0.000541
AC:
132
AN:
244000
Hom.:
0
AF XY:
0.000436
AC XY:
58
AN XY:
133090
show subpopulations
Gnomad AFR exome
AF:
0.00389
Gnomad AMR exome
AF:
0.00132
Gnomad ASJ exome
AF:
0.000101
Gnomad EAS exome
AF:
0.0000564
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000200
Gnomad OTH exome
AF:
0.00101
GnomAD4 exome
AF:
0.000253
AC:
369
AN:
1460198
Hom.:
1
Cov.:
31
AF XY:
0.000229
AC XY:
166
AN XY:
726372
show subpopulations
Gnomad4 AFR exome
AF:
0.00413
Gnomad4 AMR exome
AF:
0.00128
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000233
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000107
Gnomad4 OTH exome
AF:
0.000746
GnomAD4 genome
AF:
0.00137
AC:
208
AN:
152280
Hom.:
1
Cov.:
33
AF XY:
0.00141
AC XY:
105
AN XY:
74440
show subpopulations
Gnomad4 AFR
AF:
0.00416
Gnomad4 AMR
AF:
0.000914
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000221
Gnomad4 OTH
AF:
0.00237
Alfa
AF:
0.000581
Hom.:
0
Bravo
AF:
0.00147
EpiCase
AF:
0.000218
EpiControl
AF:
0.000238

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:4
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJun 01, 2024NRXN1: BP4 -
Likely benign, criteria provided, single submitterclinical testingAthena DiagnosticsSep 07, 2017- -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
not specified Benign:3
Likely benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoApr 24, 2017- -
Benign, criteria provided, single submitterclinical testingGeneDxJan 22, 2013This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Oct 06, 2015- -
Pitt-Hopkins-like syndrome 2 Benign:2
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 25, 2024- -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJun 15, 2016This alteration is classified as likely 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
7.2
DANN
Benign
0.84

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.

Other links and lift over

dbSNP: rs200248561; hg19: chr2-51254911; API