rs199960045

Positions:

chr2-51028004-C-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_001330078.2(NRXN1):c.270G>T(p.Gln90His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 1,599,618 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

NRXN1
NM_001330078.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 3.28

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 Likely_benign. Variant got -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3493304).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRXN1	NM_001330078.2 linkuse as main transcript	c.270G>T	p.Gln90His	missense_variant	2/23	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.270G>T	p.Gln90His	missense_variant	2/23	5	NM_001330078.2	ENSP00000385017	A1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000566

AC:

AN:

229654

Hom.:

AF XY:

0.0000393

AC XY:

AN XY:

127144

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000176

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000286

Gnomad OTH exome

AF:

0.000702

GnomAD4 exome

AF:

0.000106

AC:

154

AN:

1447406

Hom.:

Cov.:

AF XY:

0.0000875

AC XY:

AN XY:

720070

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000135

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000125

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000143

Hom.:

Bravo

AF:

0.000125

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.0000167

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 14, 2015	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2018

The p.Q90H variant (also known as c.270G>T), located in coding exon 1 of the NRXN1 gene, results from a G to T substitution at nucleotide position 270. The glutamine at codon 90 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and histidine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

See cases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Aug 13, 2021

ACMG classification criteria: BP4 -

Pitt-Hopkins-like syndrome 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 27, 2023

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 90 of the NRXN1 protein (p.Gln90His). This variant is present in population databases (rs199960045, gnomAD 0.01%). 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: 195130). 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. -

Pitt-Hopkins-like syndrome 2;C3808494:Chromosome 2p16.3 deletion syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

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

Eigen

Benign

-0.0048

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.92

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

M_CAP

Benign

0.042

MetaRNN

Benign

0.35

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

MetaSVM

Benign

-0.59

MutationAssessor

Benign

1.4

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

MutationTaster

Benign

0.98

N;N;N;N;N;N;N

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.8

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

REVEL

Uncertain

0.39

Sift

Benign

0.031

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

Sift4G

Uncertain

0.039

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

Polyphen

0.93, 0.023

.;P;B;.;.;.;.;.;.;.

Vest4

0.33

MutPred

0.65

Gain of methylation at R88 (P = 0.0469);Gain of methylation at R88 (P = 0.0469);Gain of methylation at R88 (P = 0.0469);Gain of methylation at R88 (P = 0.0469);Gain of methylation at R88 (P = 0.0469);Gain of methylation at R88 (P = 0.0469);Gain of methylation at R88 (P = 0.0469);Gain of methylation at R88 (P = 0.0469);Gain of methylation at R88 (P = 0.0469);Gain of methylation at R88 (P = 0.0469);

MVP

0.41

MPC

0.58

ClinPred

0.062

GERP RS

5.0

Varity_R

0.20

gMVP

0.71

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

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