2-50538274-G-T

Position:

chr2-50538274-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 4.92

Variant links:

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]

NRXN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRXN1	NM_001330078.2 linkuse as main transcript	c.2122C>A	p.Leu708Ile	missense_variant	10/23	ENST00000401669.7	NP_001317007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRXN1	ENST00000401669.7 linkuse as main transcript	c.2122C>A	p.Leu708Ile	missense_variant	10/23	5	NM_001330078.2	ENSP00000385017	A1

Frequencies

GnomAD3 genomes

AF:

0.00446

AC:

679

AN:

152178

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00395

AC XY:

532

AN XY:

134646

show subpopulations

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.:

Cov.:

AF XY:

0.00506

AC XY:

3675

AN XY:

726064

show subpopulations

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.:

Cov.:

AF XY:

0.00447

AC XY:

333

AN XY:

74472

show subpopulations

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.:

Bravo

AF:

0.00412

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.00101

AC:

ESP6500EA

AF:

0.00722

AC:

ExAC

AF:

0.00388

AC:

469

Asia WGS

AF:

0.00144

AC:

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

LINK: link

Submissions by phenotype

not provided

Benign:4

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) -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 13, 2016	- -
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	- -

not specified

Benign:2

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

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	Labcorp Genetics (formerly Invitae), Labcorp	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

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

.;T;.;.;T;.;.;T

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

D;D;D;D;D;D;D;D

M_CAP

Benign

0.015

MetaRNN

Benign

0.014

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.46

MutationAssessor

Benign

0.28

.;N;.;.;.;.;.;.

MutationTaster

Benign

0.62

N;N;N;N;N;N

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.1

.;N;N;N;.;.;N;.

REVEL

Uncertain

0.30

Sift

Benign

0.30

.;T;T;T;.;.;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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over