11-64648763-C-T

Position:

chr11-64648763-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_015080.4(NRXN2):c.3254G>A(p.Arg1085His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

NRXN2
NM_015080.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.59

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 links:

NRXN2-AS1 (HGNC:):

NRXN2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.33724537).

BS2

High AC in GnomAdExome4 at 44 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRXN2	NM_015080.4 linkuse as main transcript	c.3254G>A	p.Arg1085His	missense_variant	16/23	ENST00000265459.11	NP_055895.1	Q9P2S2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NRXN2	ENST00000265459.11 linkuse as main transcript	c.3254G>A	p.Arg1085His	missense_variant	16/23	5	NM_015080.4	ENSP00000265459.5	Q9P2S2-1
NRXN2	ENST00000704782.1 linkuse as main transcript	c.3263G>A	p.Arg1088His	missense_variant	15/22			ENSP00000516031.1	A0A994J5C3
NRXN2	ENST00000704781.1 linkuse as main transcript	c.3263G>A	p.Arg1088His	missense_variant	15/22			ENSP00000516029.1	A0A994J4N8

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251330

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135866

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1461788

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000342

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

NRXN2-associated Neurodevelopmental disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Feb 05, 2021

The c.3254G>A (p.Arg1085His) variant identified in the NRXN2 gene substitutes a moderately conserved Arginine for Histidine at amino acid 1085/1713 (exon 16/23). This variant is specific to the NRXN2 alpha transcript and is not present in the NRXN2beta isoform [For Review, PMID:33191396]. This variant is found with low frequency in gnomAD(v3.1) (2 heterozygotes, 0 homozygotes; allele frequency: 1.31e-5) suggesting it is not a common benign variant in the populations represented in that database. This variant is previously reported by the New York Genome Center in ClinVar (VarID:978098) as a Variant of Uncertain Significance, and to our current knowledge has not been reported in affected individuals in the literature. The p.Arg1085 residue is within the Laminin G-like 5 domain of NRXN2 (UniProtKB:Q9P2S2). Given the lack of compelling evidence for its pathogenicity, the c.3254G>A (p.Arg1085His) variant identified in the NRXN2 gene is reported as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.031

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.068

T;.;T;.

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Benign

0.74

LIST_S2

Pathogenic

0.99

.;D;D;D

M_CAP

Benign

0.032

MetaRNN

Benign

0.34

T;T;T;T

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

1.5

L;.;L;.

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.1

D;D;D;D

REVEL

Uncertain

0.43

Sift

Benign

0.17

T;T;T;T

Sift4G

Benign

0.066

T;T;T;T

Polyphen

1.0

D;D;D;.

Vest4

0.41

MVP

0.53

MPC

1.8

ClinPred

0.95

GERP RS

4.2

Varity_R

0.17

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over