rs200490872

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001330078.2(NRXN1):c.668G>A(p.Gly223Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,594,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G223G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

NRXN1
NM_001330078.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.05

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
chromosome 2p16.3 deletion syndrome
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Pitt-Hopkins-like syndrome 2
Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
autism
Inheritance: AD Classification: MODERATE Submitted by: G2P
schizophrenia
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

NRXN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16974938).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRXN1	NM_001330078.2 link	c.668G>A	p.Gly223Asp	missense_variant	Exon 2 of 23	ENST00000401669.7	NP_001317007.1	E7ERL8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRXN1	ENST00000401669.7 link	c.668G>A	p.Gly223Asp	missense_variant	Exon 2 of 23	5	NM_001330078.2	ENSP00000385017.2		E7ERL8

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000111

AC:

AN:

1441994

Hom.:

Cov.:

AF XY:

0.00000419

AC XY:

AN XY:

715480

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32990

American (AMR)

AF:

0.00

AC:

AN:

42276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25674

East Asian (EAS)

AF:

0.00

AC:

AN:

38356

South Asian (SAS)

AF:

0.00

AC:

AN:

83706

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51020

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.0000136

AC:

AN:

1102682

Other (OTH)

AF:

0.0000168

AC:

AN:

59558

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41468

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5140

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000283

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 10, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.0031

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

Eigen

Benign

-0.24

Eigen_PC

Benign

0.0077

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.95

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

M_CAP

Benign

0.015

MetaRNN

Benign

0.17

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

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.0

L;L;L;.;.;.;.;.;.;.;.

PhyloP100

3.0

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.080

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

REVEL

Benign

0.18

Sift

Benign

0.86

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

Sift4G

Benign

0.19

T;T;T;T;T;T;T;D;T;.;T

Polyphen

0.0030, 0.0

.;B;B;.;.;.;.;.;.;.;.

Vest4

0.56

MutPred

0.39

Gain of catalytic residue at G223 (P = 0.2871);Gain of catalytic residue at G223 (P = 0.2871);Gain of catalytic residue at G223 (P = 0.2871);Gain of catalytic residue at G223 (P = 0.2871);Gain of catalytic residue at G223 (P = 0.2871);Gain of catalytic residue at G223 (P = 0.2871);Gain of catalytic residue at G223 (P = 0.2871);.;Gain of catalytic residue at G223 (P = 0.2871);Gain of catalytic residue at G223 (P = 0.2871);Gain of catalytic residue at G223 (P = 0.2871);

MVP

0.86

MPC

0.78

ClinPred

0.37

GERP RS

4.8

PromoterAI

0.013

Neutral

(source)

Varity_R

0.084

gMVP

0.80

Mutation Taster

=66/34

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over