rs1045874

chr2-51027763-G-Achr2-51027763-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001330078.2(NRXN1):c.511C>T(p.Leu171=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0978 in 1,611,952 control chromosomes in the GnomAD database, including 13,137 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (4220 hom., cov: 33)
  • Exomes 𝑓: 0.089 (8917 hom.)
• Consequence: NRXN1 NM_001330078.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.80

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=-0.51).
• BP6: Variant 2-51027763-G-A is Benign according to our data. Variant chr2-51027763-G-A is described in ClinVar as [Benign]. Clinvar id is 93603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-51027763-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.8 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRXN1	NM_001330078.2	c.511C>T	p.Leu171=	synonymous_variant	2/23	ENST00000401669.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRXN1	ENST00000401669.7	c.511C>T	p.Leu171=	synonymous_variant	2/23	5	NM_001330078.2	A1

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27078 AN: 152046 Hom.: 4205 Cov.: 33

Gnomad AFR AF: 0.422

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.0976

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.0679

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.0750

Gnomad OTH AF: 0.174

GnomAD3 exomes AF: 0.113 AC: 27624 AN: 243570 Hom.: 2588 AF XY: 0.113 AC XY: 15067 AN XY: 132822

Gnomad AFR exome AF: 0.436

Gnomad AMR exome AF: 0.0660

Gnomad ASJ exome AF: 0.123

Gnomad EAS exome AF: 0.132

Gnomad SAS exome AF: 0.169

Gnomad FIN exome AF: 0.0677

Gnomad NFE exome AF: 0.0752

Gnomad OTH exome AF: 0.103

GnomAD4 exome AF: 0.0894 AC: 130504 AN: 1459788 Hom.: 8917 Cov.: 32 AF XY: 0.0913 AC XY: 66298 AN XY: 726114

Gnomad4 AFR exome AF: 0.448

Gnomad4 AMR exome AF: 0.0707

Gnomad4 ASJ exome AF: 0.124

Gnomad4 EAS exome AF: 0.106

Gnomad4 SAS exome AF: 0.169

Gnomad4 FIN exome AF: 0.0688

Gnomad4 NFE exome AF: 0.0712

Gnomad4 OTH exome AF: 0.112

GnomAD4 genome AF: 0.178 AC: 27136 AN: 152164 Hom.: 4220 Cov.: 33 AF XY: 0.177 AC XY: 13131 AN XY: 74386

Gnomad4 AFR AF: 0.422

Gnomad4 AMR AF: 0.0975

Gnomad4 ASJ AF: 0.115

Gnomad4 EAS AF: 0.120

Gnomad4 SAS AF: 0.167

Gnomad4 FIN AF: 0.0679

Gnomad4 NFE AF: 0.0750

Gnomad4 OTH AF: 0.177

Alfa AF: 0.107 Hom.: 756

Bravo AF: 0.192

Asia WGS AF: 0.172 AC: 600 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Pitt-Hopkins-like syndrome 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2016

This alteration is classified as 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	7.7
Dann	Benign	0.91

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: rs1045874; hg19: chr2-51254901; COSMIC: COSV68016073; COSMIC: COSV68016073;