11-64713324-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_015080.4(NRXN2):c.376C>G(p.Leu126Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000027 in 1,371,100 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L126M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

NRXN2
NM_015080.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.56

Publications

1 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRXN2	NM_015080.4 link	c.376C>G	p.Leu126Val	missense_variant	Exon 2 of 23	ENST00000265459.11	NP_055895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
NRXN2	ENST00000265459.11 link	c.376C>G	p.Leu126Val	missense_variant	Exon 2 of 23	5	NM_015080.4	ENSP00000265459.5
NRXN2	ENST00000704782.1 link	c.376C>G	p.Leu126Val	missense_variant	Exon 1 of 22			ENSP00000516031.1
NRXN2	ENST00000704781.1 link	c.376C>G	p.Leu126Val	missense_variant	Exon 1 of 22			ENSP00000516029.1

Frequencies

GnomAD3 genomes

AF:

0.0000527

AC:

AN:

151662

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:

0.000965

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000479

GnomAD4 exome

AF:

0.0000238

AC:

AN:

1219330

Hom.:

Cov.:

AF XY:

0.0000235

AC XY:

AN XY:

595274

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24056

American (AMR)

AF:

0.00

AC:

AN:

11438

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17290

East Asian (EAS)

AF:

0.000223

AC:

AN:

26938

South Asian (SAS)

AF:

0.000128

AC:

AN:

54490

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29468

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3540

European-Non Finnish (NFE)

AF:

0.00000200

AC:

AN:

1002192

Other (OTH)

AF:

0.000280

AC:

AN:

49918

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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:

0.0000527

AC:

AN:

151770

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

74196

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41512

American (AMR)

AF:

0.00

AC:

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000968

AC:

AN:

5164

South Asian (SAS)

AF:

0.000414

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10362

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67874

Other (OTH)

AF:

0.000474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

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:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 20, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.376C>G (p.L126V) alteration is located in exon 2 (coding exon 1) of the NRXN2 gene. This alteration results from a C to G substitution at nucleotide position 376, causing the leucine (L) at amino acid position 126 to be replaced by a valine (V). 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

0.25

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.045

T;.;T;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.93

.;D;D;D

M_CAP

Pathogenic

0.75

MetaRNN

Uncertain

0.55

D;D;D;D

MetaSVM

Uncertain

0.79

MutationAssessor

Pathogenic

3.0

M;M;M;.

PhyloP100

2.6

PrimateAI

Pathogenic

0.96

PROVEAN

Benign

-2.1

N;N;N;N

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.19

MutPred

0.71

Gain of MoRF binding (P = 0.0933);Gain of MoRF binding (P = 0.0933);Gain of MoRF binding (P = 0.0933);Gain of MoRF binding (P = 0.0933);

MVP

0.83

MPC

0.62

ClinPred

0.92

GERP RS

3.5

PromoterAI

-0.0022

Neutral

(source)

Varity_R

0.62

gMVP

0.57

Mutation Taster

=59/41

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over