chr11-64713102-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_015080.4(NRXN2):c.598G>A(p.Ala200Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 1,333,942 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0010 ( 2 hom., cov: 34)

Exomes 𝑓: 0.0018 ( 2 hom. )

Consequence

NRXN2
NM_015080.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.17

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: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005836159).

BP6

Variant 11-64713102-C-T is Benign according to our data. Variant chr11-64713102-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 211712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRXN2	NM_015080.4 link	c.598G>A	p.Ala200Thr	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.598G>A	p.Ala200Thr	missense_variant	Exon 2 of 23	5	NM_015080.4	ENSP00000265459.5	Q9P2S2-1
NRXN2	ENST00000704782.1 link	c.598G>A	p.Ala200Thr	missense_variant	Exon 1 of 22			ENSP00000516031.1	A0A994J5C3
NRXN2	ENST00000704781.1 link	c.598G>A	p.Ala200Thr	missense_variant	Exon 1 of 22			ENSP00000516029.1	A0A994J4N8

Frequencies

GnomAD3 genomes

AF:

0.00105

AC:

159

AN:

151558

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.0252

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:

0.00181

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000719

AC:

AN:

27812

AF XY:

0.000888

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:

0.00161

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00177

AC:

2089

AN:

1182276

Hom.:

Cov.:

AF XY:

0.00169

AC XY:

973

AN XY:

576432

show subpopulations

African (AFR)

AF:

0.000430

AC:

AN:

23282

American (AMR)

AF:

0.0000949

AC:

AN:

10532

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17292

East Asian (EAS)

AF:

0.00

AC:

AN:

26198

South Asian (SAS)

AF:

0.00

AC:

AN:

44596

European-Finnish (FIN)

AF:

0.0000366

AC:

AN:

27334

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3510

European-Non Finnish (NFE)

AF:

0.00203

AC:

1992

AN:

981620

Other (OTH)

AF:

0.00177

AC:

AN:

47912

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

125

249

374

498

623

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

258

344

430

<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:

0.00105

AC:

159

AN:

151666

Hom.:

Cov.:

AF XY:

0.000782

AC XY:

AN XY:

74132

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41486

American (AMR)

AF:

0.00

AC:

AN:

15218

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10366

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00181

AC:

123

AN:

67830

Other (OTH)

AF:

0.00

AC:

AN:

2102

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

Genome Hom

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:

0.00139

Hom.:

Bravo

AF:

0.00113

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Nov 08, 2016

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

NRXN2-related disorder

Benign:1

Mar 01, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.52

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0028

T;.;T;.

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.58

LIST_S2

Uncertain

0.92

.;D;D;D

M_CAP

Pathogenic

0.50

MetaRNN

Benign

0.0058

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.55

N;N;N;.

PhyloP100

2.2

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.18

N;N;N;N

REVEL

Benign

0.029

Sift

Benign

0.58

T;T;T;T

Sift4G

Benign

0.54

T;T;T;T

Polyphen

0.022

B;B;B;.

Vest4

0.11

MutPred

0.32

Gain of glycosylation at A200 (P = 0.0155);Gain of glycosylation at A200 (P = 0.0155);Gain of glycosylation at A200 (P = 0.0155);Gain of glycosylation at A200 (P = 0.0155);

MVP

0.068

MPC

0.60

ClinPred

0.056

GERP RS

3.3

PromoterAI

-0.047

Neutral

(source)

Varity_R

0.071

gMVP

0.15

Mutation Taster

=99/1

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