Variant 2-50538388-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_001330078.2(NRXN1):c.2008C>G(p.Pro670Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,694 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

NRXN1
NM_001330078.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.85

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:

NRXN1 (HGNC:):

NRXN1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRXN1	NM_001330078.2 linkuse as main transcript	c.2008C>G	p.Pro670Ala	missense_variant	10/23	ENST00000401669.7	NP_001317007.1	E7ERL8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRXN1	ENST00000401669.7 linkuse as main transcript	c.2008C>G	p.Pro670Ala	missense_variant	10/23	5	NM_001330078.2	ENSP00000385017.2		E7ERL8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

249346

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

135260

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000354

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461694

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727126

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 02, 2016

- -

Pitt-Hopkins-like syndrome 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 22, 2023

This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 710 of the NRXN1 protein (p.Pro710Ala). This variant is present in population databases (rs762326241, gnomAD 0.004%). 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: 193837). 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 disruptive. 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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.075

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

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

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

M_CAP

Benign

0.062

MetaRNN

Uncertain

0.69

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

MetaSVM

Uncertain

-0.16

MutationAssessor

Benign

1.5

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

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-2.8

.;D;D;D;.;.;.;.

REVEL

Uncertain

0.50

Sift

Uncertain

0.022

.;D;D;D;.;.;.;.

Sift4G

Uncertain

0.039

D;D;D;D;D;D;T;T

Polyphen

0.96

.;.;D;.;.;.;.;.

Vest4

0.71

MutPred

0.44

.;Loss of methylation at K669 (P = 0.0831);.;Loss of methylation at K669 (P = 0.0831);.;.;.;.;

MVP

0.33

MPC

0.75

ClinPred

0.88

GERP RS

5.2

Varity_R

0.19

gMVP

0.60

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