rs56086732

chr2-50538274-G-T

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.2122C>A(p.Leu708Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00499 in 1,612,464 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (28 hom.)
• Consequence: NRXN1 NM_001330078.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.92

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=0.014493406).
• BP6: Variant 2-50538274-G-T is Benign according to our data. Variant chr2-50538274-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 93589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-50538274-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00446 (679/152296) while in subpopulation AMR AF= 0.007 (107/15290). AF 95% confidence interval is 0.00604. There are 3 homozygotes in gnomad4. There are 333 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRXN1	NM_001330078.2	c.2122C>A	p.Leu708Ile	missense_variant	10/23	ENST00000401669.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRXN1	ENST00000401669.7	c.2122C>A	p.Leu708Ile	missense_variant	10/23	5	NM_001330078.2	A1

Frequencies

GnomAD3 genomes AF: 0.00446 AC: 679 AN: 152178 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00701

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00622

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00654

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00384 AC: 954 AN: 248338 Hom.: 6 AF XY: 0.00395 AC XY: 532 AN XY: 134646

Gnomad AFR exome AF: 0.000840

Gnomad AMR exome AF: 0.00325

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00151

Gnomad FIN exome AF: 0.00554

Gnomad NFE exome AF: 0.00569

Gnomad OTH exome AF: 0.00381

GnomAD4 exome AF: 0.00505 AC: 7373 AN: 1460168 Hom.: 28 Cov.: 31 AF XY: 0.00506 AC XY: 3675 AN XY: 726064

Gnomad4 AFR exome AF: 0.000688

Gnomad4 AMR exome AF: 0.00362

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00138

Gnomad4 FIN exome AF: 0.00497

Gnomad4 NFE exome AF: 0.00585

Gnomad4 OTH exome AF: 0.00489

GnomAD4 genome AF: 0.00446 AC: 679 AN: 152296 Hom.: 3 Cov.: 32 AF XY: 0.00447 AC XY: 333 AN XY: 74472

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00700

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00622

Gnomad4 NFE AF: 0.00654

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00518 Hom.: 6

Bravo AF: 0.00412

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00101 AC: 4

ESP6500EA AF: 0.00722 AC: 60

ExAC AF: 0.00388 AC: 469

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00649

EpiControl AF: 0.00760

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	NRXN1: BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 13, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2019	This variant is associated with the following publications: (PMID: 23769996, 28289584, 18179900, 21288692, 18728070, 23935565) -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 25, 2012	- -

Pitt-Hopkins-like syndrome 2 Benign:2

Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2021

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.014	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.46	T
MutationTaster	Benign	0.62	N;N;N;N;N;N
PrimateAI	Pathogenic	0.86	D
Sift4G	Benign	0.21	T;T;T;T;T;T;T;T
Polyphen		0.57	.;.;P;.;.;.;.;.
Vest4		0.51
MVP		0.41
MPC		0.64
ClinPred		0.010	T
GERP RS		5.1
Varity_R		0.27
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs56086732; hg19: chr2-50765412; COSMIC: COSV58453863; COSMIC: COSV58453863;