rs78540316

chr2-50620057-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001330078.2(NRXN1):c.1285C>T(p.Pro429Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0034 in 1,609,946 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P429L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (24 hom.)
• Consequence: NRXN1 NM_001330078.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 10.0

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011325926).
• BP6: Variant 2-50620057-G-A is Benign according to our data. Variant chr2-50620057-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 93585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-50620057-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00312 (475/152246) while in subpopulation NFE AF= 0.00332 (226/68026). AF 95% confidence interval is 0.00297. There are 1 homozygotes in gnomad4. There are 260 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRXN1	NM_001330078.2	c.1285C>T	p.Pro429Ser	missense_variant	8/23	ENST00000401669.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRXN1	ENST00000401669.7	c.1285C>T	p.Pro429Ser	missense_variant	8/23	5	NM_001330078.2	A1

Frequencies

GnomAD3 genomes AF: 0.00312 AC: 475 AN: 152128 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0143

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00332

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00373 AC: 915 AN: 245262 Hom.: 5 AF XY: 0.00362 AC XY: 482 AN XY: 133070

Gnomad AFR exome AF: 0.000650

Gnomad AMR exome AF: 0.000565

Gnomad ASJ exome AF: 0.0143

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00139

Gnomad FIN exome AF: 0.0155

Gnomad NFE exome AF: 0.00306

Gnomad OTH exome AF: 0.00525

GnomAD4 exome AF: 0.00343 AC: 5004 AN: 1457700 Hom.: 24 Cov.: 30 AF XY: 0.00335 AC XY: 2426 AN XY: 725086

Gnomad4 AFR exome AF: 0.000360

Gnomad4 AMR exome AF: 0.00115

Gnomad4 ASJ exome AF: 0.0136

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00151

Gnomad4 FIN exome AF: 0.0149

Gnomad4 NFE exome AF: 0.00310

Gnomad4 OTH exome AF: 0.00374

GnomAD4 genome AF: 0.00312 AC: 475 AN: 152246 Hom.: 1 Cov.: 32 AF XY: 0.00349 AC XY: 260 AN XY: 74434

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0143

Gnomad4 NFE AF: 0.00332

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00306 Hom.: 3

Bravo AF: 0.00197

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000508 AC: 2

ESP6500EA AF: 0.00383 AC: 32

ExAC AF: 0.00353 AC: 427

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 11, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 17, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2016	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 Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 14, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 18, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	NRXN1: BS2 -

Pitt-Hopkins-like syndrome 2 Benign:3

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). 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. -
Likely benign, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Jul 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 20, 2018

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, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 06, 2019

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
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Uncertain	0.11
Cadd	Pathogenic	30
Dann	Uncertain	1.0
Eigen	Uncertain	0.62
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;T
MetaRNN	Benign	0.011	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.48	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;D;.;.;.;.;.;.;.
Vest4		0.74
MVP		0.51
MPC		0.89
ClinPred		0.034	T
GERP RS		6.2
Varity_R		0.45
gMVP		0.49

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: rs78540316; hg19: chr2-50847195; COSMIC: COSV105227047; COSMIC: COSV105227047;