Variant 2-50346870-GCGCCGCCGCCGCCGCCGC-GCGCCGCCGCCGCCGCCGCCGC details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS1

The NM_001330092.2(NRXN1):c.77_79dupGCG(p.Gly26dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000751 in 1,366,766 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00068 ( 1 hom. )

Consequence

NRXN1
NM_001330092.2 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 1.48

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP6

Variant 2-50346870-G-GCGC is Benign according to our data. Variant chr2-50346870-G-GCGC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 282592.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1, Likely_benign=3}.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0013 (196/150480) while in subpopulation EAS AF= 0.00276 (14/5078). AF 95% confidence interval is 0.00167. There are 0 homozygotes in gnomad4. There are 103 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRXN1	NM_001330078.2 link	c.3365-109903_3365-109901dupGCG		intron_variant	Intron 17 of 22	ENST00000401669.7	NP_001317007.1	E7ERL8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRXN1	ENST00000401669.7 link	c.3365-109903_3365-109901dupGCG		intron_variant	Intron 17 of 22	5	NM_001330078.2	ENSP00000385017.2		E7ERL8

Frequencies

GnomAD3 genomes

AF:

0.00130

AC:

195

AN:

150380

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00177

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00119

Gnomad ASJ

AF:

0.00261

Gnomad EAS

AF:

0.00275

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.000299

Gnomad MID

AF:

0.0223

Gnomad NFE

AF:

0.000875

Gnomad OTH

AF:

0.00193

GnomAD4 exome

AF:

0.000683

AC:

831

AN:

1216286

Hom.:

Cov.:

AF XY:

0.000711

AC XY:

423

AN XY:

594980

show subpopulations

Gnomad4 AFR exome

AF:

0.00204

Gnomad4 AMR exome

AF:

0.000706

Gnomad4 ASJ exome

AF:

0.00113

Gnomad4 EAS exome

AF:

0.000785

Gnomad4 SAS exome

AF:

0.000784

Gnomad4 FIN exome

AF:

0.0000766

Gnomad4 NFE exome

AF:

0.000632

Gnomad4 OTH exome

AF:

0.000791

GnomAD4 genome

AF:

0.00130

AC:

196

AN:

150480

Hom.:

Cov.:

AF XY:

0.00140

AC XY:

103

AN XY:

73468

show subpopulations

Gnomad4 AFR

AF:

0.00179

Gnomad4 AMR

AF:

0.00119

Gnomad4 ASJ

AF:

0.00261

Gnomad4 EAS

AF:

0.00276

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.000299

Gnomad4 NFE

AF:

0.000875

Gnomad4 OTH

AF:

0.00191

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Jul 19, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 02, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29619247) -

Inborn genetic diseases

Benign:1

Jan 26, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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. -

Pitt-Hopkins-like syndrome 2

Benign:1

Apr 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

NRXN1-related disorder

Benign:1

Jan 28, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

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

Benign:1

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NRXN1 NM_138735.4 exon 1 p.Gly26dup (c.77_79dup): This variant has been reported in the literature in 1 individual with epilepsy (Friedman 2018 PMID:29619247). This variant is present in 0.1% (15/13472) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/2-50346870-G-GCGC?dataset=gnomad_r3). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant represents an in-frame duplication of 1 Glycine amino acid at position 26 within a repeat region and is not predicted to alter the reading frame. However, the effect of this variant on the protein is unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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