2-51027685-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001330078.2(NRXN1):c.589G>A(p.Val197Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,451,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V197L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NRXN1
NM_001330078.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0830

Publications

2 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07505506).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330078.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NRXN1	NM_001330078.2	MANE Select	c.589G>A	p.Val197Met	missense	Exon 2 of 23	NP_001317007.1
NRXN1	NM_001135659.3		c.589G>A	p.Val197Met	missense	Exon 2 of 24	NP_001129131.1
NRXN1	NM_001330093.2		c.589G>A	p.Val197Met	missense	Exon 2 of 23	NP_001317022.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NRXN1	ENST00000401669.7	TSL:5 MANE Select	c.589G>A	p.Val197Met	missense	Exon 2 of 23	ENSP00000385017.2
NRXN1	ENST00000404971.5	TSL:1	c.589G>A	p.Val197Met	missense	Exon 2 of 24	ENSP00000385142.1
NRXN1	ENST00000625672.2	TSL:1	c.589G>A	p.Val197Met	missense	Exon 1 of 21	ENSP00000485887.1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000130

AC:

AN:

230710

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000742

Gnomad AMR exome

AF:

0.0000303

Gnomad ASJ exome

AF:

0.000105

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000207

AC:

AN:

1451838

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

721132

show subpopulations

African (AFR)

AF:

0.0000301

AC:

AN:

33174

American (AMR)

AF:

0.0000229

AC:

AN:

43630

Ashkenazi Jewish (ASJ)

AF:

0.0000387

AC:

AN:

25860

East Asian (EAS)

AF:

0.00

AC:

AN:

39160

South Asian (SAS)

AF:

0.00

AC:

AN:

84694

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52468

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107152

Other (OTH)

AF:

0.00

AC:

AN:

59942

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000329

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41466

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5142

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:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000254

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Pitt-Hopkins-like syndrome 2

Uncertain:1

Feb 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 197 of the NRXN1 protein (p.Val197Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with NRXN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1375016). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0082

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.12

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.018

MetaRNN

Benign

0.075

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.1

PhyloP100

-0.083

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.14

REVEL

Benign

0.10

Sift

Benign

0.090

Sift4G

Uncertain

0.010

Polyphen

0.83

Vest4

0.46

MutPred

0.19

Gain of MoRF binding (P = 0.1516)

MVP

0.32

MPC

0.61

ClinPred

0.093

GERP RS

0.96

PromoterAI

0.024

Neutral

(source)

Varity_R

0.033

gMVP

0.26

Mutation Taster

=82/18

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over