2-50346870-GCGCCGCCGCCGCCGCCGCCGC-GCGCCGC

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBA1

The ENST00000342183.9(NRXN1):c.65_79delGCGGCGGCGGCGGCG(p.Gly22_Gly26del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00361 in 1,366,786 control chromosomes in the GnomAD database, including 340 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 38 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 302 hom. )

Consequence

NRXN1
ENST00000342183.9 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

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 -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in ENST00000342183.9

BP6

Variant 2-50346870-GCGCCGCCGCCGCCGC-G is Benign according to our data. Variant chr2-50346870-GCGCCGCCGCCGCCGC-G is described in ClinVar as Benign. ClinVar VariationId is 287918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0652 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRXN1	NM_001330078.2 link	c.3365-109915_3365-109901delGCGGCGGCGGCGGCG		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.3365-109915_3365-109901delGCGGCGGCGGCGGCG		intron_variant	Intron 17 of 22	5	NM_001330078.2	ENSP00000385017.2		E7ERL8

Frequencies

GnomAD3 genomes

AF:

0.0146

AC:

2202

AN:

150380

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0489

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00523

Gnomad ASJ

AF:

0.00696

Gnomad EAS

AF:

0.00412

Gnomad SAS

AF:

0.000623

Gnomad FIN

AF:

0.0000998

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000460

Gnomad OTH

AF:

0.0145

GnomAD2 exomes

AF:

0.00797

AC:

597

AN:

74950

AF XY:

0.00662

show subpopulations

Gnomad AFR exome

AF:

0.196

Gnomad AMR exome

AF:

0.0111

Gnomad ASJ exome

AF:

0.0133

Gnomad EAS exome

AF:

0.0140

Gnomad FIN exome

AF:

0.0000876

Gnomad NFE exome

AF:

0.00116

Gnomad OTH exome

AF:

0.00378

GnomAD4 exome

AF:

0.00224

AC:

2726

AN:

1216306

Hom.:

302

AF XY:

0.00204

AC XY:

1216

AN XY:

594990

show subpopulations

African (AFR)

AF:

0.0679

AC:

1730

AN:

25488

American (AMR)

AF:

0.00750

AC:

117

AN:

15590

Ashkenazi Jewish (ASJ)

AF:

0.00948

AC:

184

AN:

19416

East Asian (EAS)

AF:

0.00257

AC:

AN:

28040

South Asian (SAS)

AF:

0.000515

AC:

AN:

44622

European-Finnish (FIN)

AF:

0.000179

AC:

AN:

39150

Middle Eastern (MID)

AF:

0.000761

AC:

AN:

3942

European-Non Finnish (NFE)

AF:

0.000357

AC:

354

AN:

990752

Other (OTH)

AF:

0.00479

AC:

236

AN:

49306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.576

Heterozygous variant carriers

132

198

264

330

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<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:

0.0147

AC:

2205

AN:

150480

Hom.:

Cov.:

AF XY:

0.0141

AC XY:

1038

AN XY:

73468

show subpopulations

African (AFR)

AF:

0.0488

AC:

2015

AN:

41300

American (AMR)

AF:

0.00523

AC:

AN:

15118

Ashkenazi Jewish (ASJ)

AF:

0.00696

AC:

AN:

3448

East Asian (EAS)

AF:

0.00414

AC:

AN:

5078

South Asian (SAS)

AF:

0.000624

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.0000998

AC:

AN:

10018

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000460

AC:

AN:

67418

Other (OTH)

AF:

0.0144

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

104

208

313

417

521

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.0164

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Jun 02, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Mar 21, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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

- -

NRXN1-related disorder

Benign:1

May 15, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.0

Mutation Taster

=186/14

polymorphism (auto)

(source)

Splicing

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