rs267606922

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_001330078.2(NRXN1):c.2936C>G(p.Ser979*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000685 in 1,460,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

NRXN1
NM_001330078.2 stop_gained

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 5.47

Publications

4 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: Pathogenic. The variant received 11 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-50496039-G-C is Pathogenic according to our data. Variant chr2-50496039-G-C is described in CliVar as Pathogenic. Clinvar id is 9041.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-50496039-G-C is described in CliVar as Pathogenic. Clinvar id is 9041.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-50496039-G-C is described in CliVar as Pathogenic. Clinvar id is 9041.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-50496039-G-C is described in CliVar as Pathogenic. Clinvar id is 9041.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-50496039-G-C is described in CliVar as Pathogenic. Clinvar id is 9041.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-50496039-G-C is described in CliVar as Pathogenic. Clinvar id is 9041.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-50496039-G-C is described in CliVar as Pathogenic. Clinvar id is 9041.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-50496039-G-C is described in CliVar as Pathogenic. Clinvar id is 9041.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-50496039-G-C is described in CliVar as Pathogenic. Clinvar id is 9041.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-50496039-G-C is described in CliVar as Pathogenic. Clinvar id is 9041.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-50496039-G-C is described in CliVar as Pathogenic. Clinvar id is 9041.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-50496039-G-C is described in CliVar as Pathogenic. Clinvar id is 9041.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-50496039-G-C is described in CliVar as Pathogenic. Clinvar id is 9041.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-50496039-G-C is described in CliVar as Pathogenic. Clinvar id is 9041.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-50496039-G-C is described in CliVar as Pathogenic. Clinvar id is 9041.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-50496039-G-C is described in CliVar as Pathogenic. Clinvar id is 9041.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-50496039-G-C is described in CliVar as Pathogenic. Clinvar id is 9041.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-50496039-G-C is described in CliVar as Pathogenic. Clinvar id is 9041.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-50496039-G-C is described in CliVar as Pathogenic. Clinvar id is 9041.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-50496039-G-C is described in CliVar as Pathogenic. Clinvar id is 9041.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-50496039-G-C is described in CliVar as Pathogenic. Clinvar id is 9041.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-50496039-G-C is described in CliVar as Pathogenic. Clinvar id is 9041.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRXN1	NM_001330078.2 link	c.2936C>G	p.Ser979*	stop_gained	Exon 15 of 23	ENST00000401669.7	NP_001317007.1	E7ERL8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRXN1	ENST00000401669.7 link	c.2936C>G	p.Ser979*	stop_gained	Exon 15 of 23	5	NM_001330078.2	ENSP00000385017.2		E7ERL8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000405

AC:

AN:

246666

AF XY:

0.00000748

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000896

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460582

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726424

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44588

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.00

AC:

AN:

85988

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111290

Other (OTH)

AF:

0.00

AC:

AN:

60344

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Pitt-Hopkins-like syndrome 2

Pathogenic:1

Nov 01, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.66

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.98

PhyloP100

5.5

Vest4

0.79

GERP RS

5.0

PromoterAI

0.0070

Neutral

(source)

Mutation Taster

=0/200

disease causing (ClinVar)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over