2-50346867-C-G

Position:

chr2-50346867-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001330092.2(NRXN1):c.83G>C(p.Gly28Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000046 in 1,391,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

NRXN1
NM_001330092.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.03

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017304093).

BP6

Variant 2-50346867-C-G is Benign according to our data. Variant chr2-50346867-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 378299.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000467 (58/1240670) while in subpopulation EAS AF= 0.000489 (14/28618). AF 95% confidence interval is 0.000295. There are 0 homozygotes in gnomad4_exome. There are 29 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRXN1	NM_001330078.2 linkuse as main transcript	c.3365-109897G>C		intron_variant		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.3365-109897G>C		intron_variant		5	NM_001330078.2	ENSP00000385017.2		E7ERL8

Frequencies

GnomAD3 genomes

AF:

0.0000398

AC:

AN:

150816

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:

0.000586

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000986

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000237

AC:

AN:

84426

Hom.:

AF XY:

0.000263

AC XY:

AN XY:

49340

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000272

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00288

Gnomad SAS exome

AF:

0.000703

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000259

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000467

AC:

AN:

1240670

Hom.:

Cov.:

AF XY:

0.0000477

AC XY:

AN XY:

607734

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000569

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000489

Gnomad4 SAS exome

AF:

0.000316

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000239

Gnomad4 OTH exome

AF:

0.0000794

GnomAD4 genome

AF:

0.0000398

AC:

AN:

150922

Hom.:

Cov.:

AF XY:

0.0000814

AC XY:

AN XY:

73730

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000588

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000986

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000128

ExAC

AF:

0.000125

AC:

Asia WGS

AF:

0.00116

AC:

AN:

3458

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2016

The p.G28A variant (also known as c.83G>C), located in coding exon 1 of the NRXN1 gene, results from a G to C substitution at nucleotide position 83. The glycine at codon 28 is replaced by alanine, an amino acid with similar properties. This variant has been identified in two individuals with autism spectrum disorder in the literature without a second alteration detected in the NRXN1 gene; in addition, one of these individuals was also heterozygous for a frameshift alteration in the SHANK3 gene (Yan J et al. Neurosci. Lett., 2008 Jun;438:368-70; Boccuto L et al. Eur. J. Hum. Genet., 2013 Mar;21:310-6). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 10, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.093

.;T;.

Eigen

Benign

-0.14

Eigen_PC

Benign

0.055

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.45

T;T;T

M_CAP

Benign

0.031

MetaRNN

Benign

0.017

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.34

N;N;.

PROVEAN

Benign

-0.53

N;.;.

REVEL

Benign

0.13

Sift

Benign

0.48

T;.;.

Sift4G

Benign

1.0

T;T;T

Polyphen

0.44

.;B;.

Vest4

0.40

MutPred

0.31

Gain of helix (P = 0.0225);Gain of helix (P = 0.0225);Gain of helix (P = 0.0225);

MVP

0.16

ClinPred

0.077

GERP RS

5.0

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