11-64607708-C-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_015080.4(NRXN2):c.4627G>T(p.Ala1543Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 151,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 30)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NRXN2
NM_015080.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.96

Publications

0 publications found

Variant links:

Genes affected

NRXN2 (HGNC:8009): (neurexin 2) This gene encodes a member of the neurexin gene family. The products of these genes function as cell adhesion molecules and receptors in the vertebrate nervous system. These genes utilize two promoters. The majority of transcripts are produced from the upstream promoter and encode alpha-neurexin isoforms while a smaller number of transcripts are produced from the downstream promoter and encode beta-neuresin isoforms. The alpha-neurexins contain epidermal growth factor-like (EGF-like) sequences and laminin G domains, and have been shown to interact with neurexophilins. The beta-neurexins lack EGF-like sequences and contain fewer laminin G domains than alpha-neurexins. Alternative splicing and the use of alternative promoters may generate thousands of transcript variants (PMID: 12036300, PMID: 11944992).[provided by RefSeq, Jun 2010]

NRXN2 Gene-Disease associations (from GenCC):

autism
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, G2P
neurodevelopmental disorder
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

NRXN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.050869077).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015080.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NRXN2	NM_015080.4	MANE Select	c.4627G>T	p.Ala1543Ser	missense	Exon 23 of 23	NP_055895.1	Q9P2S2-1
NRXN2	NM_138732.3		c.4417G>T	p.Ala1473Ser	missense	Exon 20 of 20	NP_620060.1	Q9P2S2-2
NRXN2	NM_138734.3		c.1489G>T	p.Ala497Ser	missense	Exon 7 of 7	NP_620063.1	P58401-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NRXN2	ENST00000265459.11	TSL:5 MANE Select	c.4627G>T	p.Ala1543Ser	missense	Exon 23 of 23	ENSP00000265459.5	Q9P2S2-1
NRXN2	ENST00000704782.1		c.4636G>T	p.Ala1546Ser	missense	Exon 22 of 22	ENSP00000516031.1	A0A994J5C3
NRXN2	ENST00000377559.7	TSL:1	c.4417G>T	p.Ala1473Ser	missense	Exon 20 of 20	ENSP00000366782.3	Q9P2S2-2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151958

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00000633

AC:

AN:

158066

AF XY:

0.00

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:

0.0000163

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

7.15e-7

AC:

AN:

1398194

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

688704

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31740

American (AMR)

AF:

0.00

AC:

AN:

36454

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24808

East Asian (EAS)

AF:

0.00

AC:

AN:

36124

South Asian (SAS)

AF:

0.00

AC:

AN:

79310

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5660

European-Non Finnish (NFE)

AF:

9.28e-7

AC:

AN:

1077642

Other (OTH)

AF:

0.00

AC:

AN:

57824

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151958

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74226

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41384

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67944

Other (OTH)

AF:

0.00

AC:

AN:

2092

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

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.:

Bravo

AF:

0.0000113

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.049

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.83

M_CAP

Benign

0.025

MetaRNN

Benign

0.051

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

2.0

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.42

REVEL

Benign

0.099

Sift

Benign

0.50

Sift4G

Benign

0.48

Polyphen

0.011

Vest4

0.040

MutPred

0.086

Gain of glycosylation at A1543 (P = 0.0135)

MVP

0.082

MPC

0.96

ClinPred

0.094

GERP RS

3.4

Varity_R

0.082

gMVP

0.20

Mutation Taster

=97/3

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over