chr2-50553020-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS1

The NM_001330078.2(NRXN1):c.1326A>C(p.Val442Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000523 in 1,605,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V442V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

NRXN1
NM_001330078.2 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -2.12

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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 2-50553020-T-G is Benign according to our data. Variant chr2-50553020-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 193624. Variant chr2-50553020-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 193624. Variant chr2-50553020-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 193624. Variant chr2-50553020-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 193624. Variant chr2-50553020-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 193624. Variant chr2-50553020-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 193624. Variant chr2-50553020-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 193624. Variant chr2-50553020-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 193624. Variant chr2-50553020-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 193624. Variant chr2-50553020-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 193624. Variant chr2-50553020-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 193624. Variant chr2-50553020-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 193624. Variant chr2-50553020-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 193624. Variant chr2-50553020-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 193624. Variant chr2-50553020-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 193624. Variant chr2-50553020-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 193624. Variant chr2-50553020-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 193624. Variant chr2-50553020-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 193624. Variant chr2-50553020-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 193624. Variant chr2-50553020-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 193624. Variant chr2-50553020-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 193624. Variant chr2-50553020-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 193624.

BP7

Synonymous conserved (PhyloP=-2.12 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000544 (79/1453296) while in subpopulation AMR AF = 0.00179 (79/44248). AF 95% confidence interval is 0.00147. There are 0 homozygotes in GnomAdExome4. There are 35 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRXN1	NM_001330078.2 link	c.1326A>C	p.Val442Val	synonymous_variant	Exon 9 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.1326A>C	p.Val442Val	synonymous_variant	Exon 9 of 23	5	NM_001330078.2	ENSP00000385017.2		E7ERL8

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000305

AC:

AN:

243002

AF XY:

0.000250

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00217

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000544

AC:

AN:

1453296

Hom.:

Cov.:

AF XY:

0.0000484

AC XY:

AN XY:

722634

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33158

American (AMR)

AF:

0.00179

AC:

AN:

44248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25862

East Asian (EAS)

AF:

0.00

AC:

AN:

39638

South Asian (SAS)

AF:

0.00

AC:

AN:

85734

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50876

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107984

Other (OTH)

AF:

0.00

AC:

AN:

60062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.0000328

AC:

AN:

152350

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41580

American (AMR)

AF:

0.000327

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000160

Hom.:

Bravo

AF:

0.000215

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Nov 18, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 03, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Oct 04, 2016

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 26, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Aug 02, 2017

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. -

Pitt-Hopkins-like syndrome 2

Benign:1

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.22

(source)

DANN

Benign

0.59

PhyloP100

-2.1

PromoterAI

0.0070

Neutral

(source)

Mutation Taster

=96/4

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over