rs56402642

Positions:

• chr2-50495930-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001330078.2(NRXN1):​c.3045C>T​(p.Ala1015=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,608,268 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (3 hom.)
• Consequence: NRXN1 NM_001330078.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: -2.96

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 2-50495930-G-A is Benign according to our data. Variant chr2-50495930-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 93597.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=3, Uncertain_significance=1}. Variant chr2-50495930-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.96 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00112 (170/152214) while in subpopulation NFE AF= 0.00184 (125/68014). AF 95% confidence interval is 0.00158. There are 0 homozygotes in gnomad4. There are 74 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRXN1	NM_001330078.2	c.3045C>T	p.Ala1015=	synonymous_variant	15/23	ENST00000401669.7	NP_001317007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRXN1	ENST00000401669.7	c.3045C>T	p.Ala1015=	synonymous_variant	15/23	5	NM_001330078.2	ENSP00000385017	A1

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 170 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00184

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00123 AC: 303 AN: 245408 Hom.: 1 AF XY: 0.00141 AC XY: 188 AN XY: 133062

Gnomad AFR exome AF: 0.000388

Gnomad AMR exome AF: 0.000796

Gnomad ASJ exome AF: 0.00113

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00124

Gnomad FIN exome AF: 0.0000470

Gnomad NFE exome AF: 0.00190

Gnomad OTH exome AF: 0.00152

GnomAD4 exome AF: 0.00163 AC: 2370 AN: 1456054 Hom.: 3 Cov.: 31 AF XY: 0.00161 AC XY: 1168 AN XY: 723748

Gnomad4 AFR exome AF: 0.000240

Gnomad4 AMR exome AF: 0.00109

Gnomad4 ASJ exome AF: 0.00174

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00153

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00183

Gnomad4 OTH exome AF: 0.00166

GnomAD4 genome AF: 0.00112 AC: 170 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.000995 AC XY: 74 AN XY: 74406

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00184

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00172 Hom.: 0

Bravo AF: 0.00126

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00231

EpiControl AF: 0.00274

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 27, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 16, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 29, 2013	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. -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	NRXN1: BP4, BP7 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 29, 2017	- -

Pitt-Hopkins-like syndrome 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2016

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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 08, 2019

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	-0.77
CADD	Benign	0.78
DANN	Benign	0.60

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: rs56402642; hg19: chr2-50723068;