Genetic Variant NRXN1:c.3364+93730T>A (chr2-50371712-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001330078.2(NRXN1):c.3364+93730T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.541 in 151,762 control chromosomes in the GnomAD database, including 23,737 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.54 ( 23737 hom., cov: 32)

Consequence

NRXN1
NM_001330078.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.28

Publications

5 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.9 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRXN1	NM_001330078.2 link	c.3364+93730T>A		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.3364+93730T>A		intron_variant	Intron 17 of 22	5	NM_001330078.2	ENSP00000385017.2		E7ERL8

Frequencies

GnomAD3 genomes

AF:

0.541

AC:

82017

AN:

151644

Hom.:

23703

Cov.:

show subpopulations

Gnomad AFR

AF:

0.704

Gnomad AMI

AF:

0.362

Gnomad AMR

AF:

0.560

Gnomad ASJ

AF:

0.392

Gnomad EAS

AF:

0.922

Gnomad SAS

AF:

0.521

Gnomad FIN

AF:

0.442

Gnomad MID

AF:

0.418

Gnomad NFE

AF:

0.436

Gnomad OTH

AF:

0.527

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.541

AC:

82109

AN:

151762

Hom.:

23737

Cov.:

AF XY:

0.542

AC XY:

40172

AN XY:

74142

show subpopulations

African (AFR)

AF:

0.704

AC:

29166

AN:

41426

American (AMR)

AF:

0.560

AC:

8524

AN:

15212

Ashkenazi Jewish (ASJ)

AF:

0.392

AC:

1354

AN:

3458

East Asian (EAS)

AF:

0.922

AC:

4765

AN:

5168

South Asian (SAS)

AF:

0.521

AC:

2516

AN:

4830

European-Finnish (FIN)

AF:

0.442

AC:

4646

AN:

10512

Middle Eastern (MID)

AF:

0.408

AC:

120

AN:

294

European-Non Finnish (NFE)

AF:

0.436

AC:

29569

AN:

67844

Other (OTH)

AF:

0.531

AC:

1120

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1783

3567

5350

7134

8917

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

698

1396

2094

2792

3490

<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:

0.502

Hom.:

2516

Bravo

AF:

0.564

Asia WGS

AF:

0.715

AC:

2487

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

(source)

DANN

Benign

0.73

PhyloP100

1.3

Mutation Taster

=100/0

polymorphism (auto)

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over