2-50346867-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The ENST00000342183.9(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. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G28V) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

NRXN1
ENST00000342183.9 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.03

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: Benign. The variant received -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 VariationId is 378299.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 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 GnomAdExome4. There are 29 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRXN1	NM_001330078.2 link	c.3365-109897G>C		intron_variant	Intron 17 of 22	ENST00000401669.7	NP_001317007.1	E7ERL8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRXN1	ENST00000401669.7 link	c.3365-109897G>C		intron_variant	Intron 17 of 22	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

GnomAD2 exomes

AF:

0.000237

AC:

AN:

84426

AF XY:

0.000263

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 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

African (AFR)

AF:

0.00

AC:

AN:

26170

American (AMR)

AF:

0.0000569

AC:

AN:

17578

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20022

East Asian (EAS)

AF:

0.000489

AC:

AN:

28618

South Asian (SAS)

AF:

0.000316

AC:

AN:

47474

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40712

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4114

European-Non Finnish (NFE)

AF:

0.0000239

AC:

AN:

1005604

Other (OTH)

AF:

0.0000794

AC:

AN:

50378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

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:

0.0000398

AC:

AN:

150922

Hom.:

Cov.:

AF XY:

0.0000814

AC XY:

AN XY:

73730

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41322

American (AMR)

AF:

0.00

AC:

AN:

15172

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3456

East Asian (EAS)

AF:

0.000588

AC:

AN:

5106

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000986

AC:

AN:

10144

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67598

Other (OTH)

AF:

0.00

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

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:

0.00

Hom.:

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

Nov 30, 2016

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Sep 10, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

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;.

PhyloP100

4.0

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

Mutation Taster

=72/28

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over