11-64648800-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_015080.4(NRXN2):​c.3217G>A​(p.Gly1073Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NRXN2
NM_015080.4 missense

Scores

12
6
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.90
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-AS1 (HGNC:40416): (NRXN2 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.943

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NRXN2NM_015080.4 linkc.3217G>A p.Gly1073Arg missense_variant Exon 16 of 23 ENST00000265459.11 NP_055895.1 Q9P2S2-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NRXN2ENST00000265459.11 linkc.3217G>A p.Gly1073Arg missense_variant Exon 16 of 23 5 NM_015080.4 ENSP00000265459.5 Q9P2S2-1
NRXN2ENST00000704782.1 linkc.3226G>A p.Gly1076Arg missense_variant Exon 15 of 22 ENSP00000516031.1 A0A994J5C3
NRXN2ENST00000704781.1 linkc.3226G>A p.Gly1076Arg missense_variant Exon 15 of 22 ENSP00000516029.1 A0A994J4N8

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461882
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 27, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.3217G>A (p.G1073R) alteration is located in exon 16 (coding exon 15) of the NRXN2 gene. This alteration results from a G to A substitution at nucleotide position 3217, causing the glycine (G) at amino acid position 1073 to be replaced by an arginine (R). 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
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.28
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.56
D;.;D;.
Eigen
Pathogenic
0.81
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Pathogenic
1.0
.;D;D;D
M_CAP
Uncertain
0.29
D
MetaRNN
Pathogenic
0.94
D;D;D;D
MetaSVM
Uncertain
0.45
D
MutationAssessor
Uncertain
2.9
M;.;M;.
PrimateAI
Pathogenic
0.89
D
PROVEAN
Pathogenic
-7.1
D;D;D;D
REVEL
Pathogenic
0.87
Sift
Uncertain
0.0010
D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
1.0
D;D;D;.
Vest4
0.92
MutPred
0.82
Loss of catalytic residue at G1073 (P = 0.0451);.;Loss of catalytic residue at G1073 (P = 0.0451);.;
MVP
0.27
MPC
1.8
ClinPred
1.0
D
GERP RS
4.5
Varity_R
0.72
gMVP
0.71

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-64416272; COSMIC: COSV55453297; COSMIC: COSV55453297; API