chr2-50053466-T-C

Position:

• chr2-50053466-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001330078.2(NRXN1):​c.3933A>G​(p.Ala1311=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00666 in 1,614,012 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0068 (49 hom.)
• Consequence: NRXN1 NM_001330078.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.957

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 2-50053466-T-C is Benign according to our data. Variant chr2-50053466-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 93602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-50053466-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.957 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00493 (751/152290) while in subpopulation AMR AF= 0.00883 (135/15294). AF 95% confidence interval is 0.00761. There are 6 homozygotes in gnomad4. There are 349 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRXN1	NM_001330078.2	c.3933A>G	p.Ala1311=	synonymous_variant	21/23	ENST00000401669.7	NP_001317007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRXN1	ENST00000401669.7	c.3933A>G	p.Ala1311=	synonymous_variant	21/23	5	NM_001330078.2	ENSP00000385017	A1

Frequencies

GnomAD3 genomes AF: 0.00494 AC: 751 AN: 152172 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.00884

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00695

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00400 AC: 1005 AN: 251110 Hom.: 4 AF XY: 0.00403 AC XY: 547 AN XY: 135716

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00324

Gnomad ASJ exome AF: 0.00764

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00642

Gnomad OTH exome AF: 0.00637

GnomAD4 exome AF: 0.00684 AC: 9993 AN: 1461722 Hom.: 49 Cov.: 32 AF XY: 0.00665 AC XY: 4839 AN XY: 727154

Gnomad4 AFR exome AF: 0.00143

Gnomad4 AMR exome AF: 0.00315

Gnomad4 ASJ exome AF: 0.00696

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000765

Gnomad4 FIN exome AF: 0.000674

Gnomad4 NFE exome AF: 0.00811

Gnomad4 OTH exome AF: 0.00704

GnomAD4 genome AF: 0.00493 AC: 751 AN: 152290 Hom.: 6 Cov.: 33 AF XY: 0.00469 AC XY: 349 AN XY: 74474

Gnomad4 AFR AF: 0.00154

Gnomad4 AMR AF: 0.00883

Gnomad4 ASJ AF: 0.00836

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.00695

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00585 Hom.: 2

Bravo AF: 0.00498

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00753

EpiControl AF: 0.00747

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 30, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	NRXN1: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 14, 2023	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2012	This 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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 19, 2016	- -

Pitt-Hopkins-like syndrome 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 21, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 25, 2022

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. -

NRXN1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 03, 2024

This variant is classified as 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	-0.53
CADD	Benign	8.0
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

Other links and lift over

dbSNP: rs79970751; hg19: chr2-50280604;