rs772811573

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_015080.4(NRXN2):c.670C>T(p.Pro224Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000419 in 1,457,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

NRXN2
NM_015080.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.86

Publications

2 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: G2P, Ambry Genetics
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 -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.046080053).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRXN2	NM_015080.4 link	c.670C>T	p.Pro224Ser	missense_variant	Exon 2 of 23	ENST00000265459.11	NP_055895.1	Q9P2S2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NRXN2	ENST00000265459.11 link	c.670C>T	p.Pro224Ser	missense_variant	Exon 2 of 23	5	NM_015080.4	ENSP00000265459.5	Q9P2S2-1
NRXN2	ENST00000704782.1 link	c.670C>T	p.Pro224Ser	missense_variant	Exon 1 of 22			ENSP00000516031.1	A0A994J5C3
NRXN2	ENST00000704781.1 link	c.670C>T	p.Pro224Ser	missense_variant	Exon 1 of 22			ENSP00000516029.1	A0A994J4N8

Frequencies

GnomAD3 genomes

AF:

0.0000724

AC:

AN:

151958

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000682

AC:

AN:

73352

AF XY:

0.0000730

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:

0.0000747

Gnomad OTH exome

AF:

0.000437

GnomAD4 exome

AF:

0.0000391

AC:

AN:

1305346

Hom.:

Cov.:

AF XY:

0.0000390

AC XY:

AN XY:

640566

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25918

American (AMR)

AF:

0.00

AC:

AN:

27344

Ashkenazi Jewish (ASJ)

AF:

0.0000464

AC:

AN:

21558

East Asian (EAS)

AF:

0.00

AC:

AN:

30110

South Asian (SAS)

AF:

0.000157

AC:

AN:

70278

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32110

Middle Eastern (MID)

AF:

0.000263

AC:

AN:

3802

European-Non Finnish (NFE)

AF:

0.0000336

AC:

AN:

1040306

Other (OTH)

AF:

0.0000556

AC:

AN:

53920

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

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:

0.0000658

AC:

AN:

152066

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41532

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10522

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

67942

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.530

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:

0.000155

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.000234

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Jul 22, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 11, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.670C>T (p.P224S) alteration is located in exon 2 (coding exon 1) of the NRXN2 gene. This alteration results from a C to T substitution at nucleotide position 670, causing the proline (P) at amino acid position 224 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.0037

T;.;T;.

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.39

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.95

.;D;D;D

M_CAP

Pathogenic

0.74

MetaRNN

Benign

0.046

T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-0.26

N;N;N;.

PhyloP100

2.9

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

0.29

N;N;N;N

REVEL

Benign

0.098

Sift

Benign

0.61

T;T;T;T

Sift4G

Uncertain

0.0050

D;D;D;D

Polyphen

0.073

B;B;B;.

Vest4

0.17

MutPred

0.50

Gain of glycosylation at P224 (P = 0.0225);Gain of glycosylation at P224 (P = 0.0225);Gain of glycosylation at P224 (P = 0.0225);Gain of glycosylation at P224 (P = 0.0225);

MVP

0.082

MPC

0.62

ClinPred

0.058

GERP RS

3.3

PromoterAI

0.034

Neutral

(source)

Varity_R

0.073

gMVP

0.31

Mutation Taster

=93/7

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