2-50346870-GCGCCGCCGCCGCCGCCGCCGC-GCGCCGCCGCCGCCGCCGC

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP3BP6_Very_Strong

The ENST00000342183.9(NRXN1):c.77_79delGCG(p.Gly26del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000722 in 1,354,980 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G26G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00010 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00080 ( 0 hom. )

Consequence

NRXN1
ENST00000342183.9 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.96

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.

BP3

Nonframeshift variant in repetitive region in ENST00000342183.9

BP6

Variant 2-50346870-GCGC-G is Benign according to our data. Variant chr2-50346870-GCGC-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 588566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRXN1	NM_001330078.2 link	c.3365-109903_3365-109901delGCG		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.3365-109903_3365-109901delGCG		intron_variant	Intron 17 of 22	5	NM_001330078.2	ENSP00000385017.2		E7ERL8

Frequencies

GnomAD3 genomes

AF:

0.0000998

AC:

AN:

150364

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000662

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000589

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000890

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000907

AC:

AN:

74950

AF XY:

0.000769

show subpopulations

Gnomad AFR exome

AF:

0.00102

Gnomad AMR exome

AF:

0.00116

Gnomad ASJ exome

AF:

0.000606

Gnomad EAS exome

AF:

0.00140

Gnomad FIN exome

AF:

0.00219

Gnomad NFE exome

AF:

0.000609

Gnomad OTH exome

AF:

0.00162

GnomAD4 exome

AF:

0.000799

AC:

963

AN:

1204616

Hom.:

AF XY:

0.000890

AC XY:

524

AN XY:

588858

show subpopulations

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

African (AFR)

AF:

0.000630

AC:

AN:

25390

American (AMR)

AF:

0.00142

AC:

AN:

15450

Ashkenazi Jewish (ASJ)

AF:

0.00125

AC:

AN:

19172

East Asian (EAS)

AF:

0.00111

AC:

AN:

27834

South Asian (SAS)

AF:

0.00395

AC:

174

AN:

44032

European-Finnish (FIN)

AF:

0.00236

AC:

AN:

38486

Middle Eastern (MID)

AF:

0.00180

AC:

AN:

3898

European-Non Finnish (NFE)

AF:

0.000567

AC:

557

AN:

981590

Other (OTH)

AF:

0.000841

AC:

AN:

48764

⚠️ 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: 0.276

Heterozygous variant carriers

120

240

361

481

601

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:

0.0000998

AC:

AN:

150364

Hom.:

Cov.:

AF XY:

0.0000682

AC XY:

AN XY:

73352

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41184

American (AMR)

AF:

0.0000662

AC:

AN:

15098

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3448

East Asian (EAS)

AF:

0.000589

AC:

AN:

5094

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10012

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000890

AC:

AN:

67416

Other (OTH)

AF:

0.00

AC:

AN:

2072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

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.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Sep 16, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.0

Mutation Taster

=77/23

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

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over