Genetic Variant NRXN2:p.Ala1562Thr (chr11-64607651-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_015080.4(NRXN2):c.4684G>A(p.Ala1562Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 30)

Consequence

NRXN2
NM_015080.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.52

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.30612946).

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.4684G>A	p.Ala1562Thr	missense	Exon 23 of 23	NP_055895.1	Q9P2S2-1
NRXN2	NM_138732.3		c.4474G>A	p.Ala1492Thr	missense	Exon 20 of 20	NP_620060.1	Q9P2S2-2
NRXN2	NM_138734.3		c.1546G>A	p.Ala516Thr	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.4684G>A	p.Ala1562Thr	missense	Exon 23 of 23	ENSP00000265459.5	Q9P2S2-1
NRXN2	ENST00000704782.1		c.4693G>A	p.Ala1565Thr	missense	Exon 22 of 22	ENSP00000516031.1	A0A994J5C3
NRXN2	ENST00000377559.7	TSL:1	c.4474G>A	p.Ala1492Thr	missense	Exon 20 of 20	ENSP00000366782.3	Q9P2S2-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

133038

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

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

Uncertain

0.50

BayesDel_addAF

Benign

-0.00055

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.18

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.31

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

1.4

PhyloP100

7.5

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-2.1

REVEL

Benign

0.22

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.048

Polyphen

1.0

Vest4

0.33

MutPred

0.076

Gain of glycosylation at A1562 (P = 0.007)

MVP

0.68

MPC

1.0

ClinPred

0.92

GERP RS

3.4

Varity_R

0.13

gMVP

0.33

Mutation Taster

=64/36

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over