11-64713651-G-C

Position:

• chr11-64713651-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_015080.4(NRXN2):​c.49C>G​(p.Leu17Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000168 in 1,222,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: NRXN2 NM_015080.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.0680

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08865678).
• BS2: High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRXN2	NM_015080.4	c.49C>G	p.Leu17Val	missense_variant	2/23	ENST00000265459.11	NP_055895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRXN2	ENST00000265459.11	c.49C>G	p.Leu17Val	missense_variant	2/23	5	NM_015080.4	ENSP00000265459	P4

Frequencies

GnomAD3 genomes AF: 0.000140 AC: 21 AN: 149682 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

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: 0.000298

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000171 AC: 4 AN: 23422 Hom.: 0 AF XY: 0.000282 AC XY: 4 AN XY: 14176

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: 0.000474

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000172 AC: 184 AN: 1072728 Hom.: 0 Cov.: 33 AF XY: 0.000194 AC XY: 100 AN XY: 514532

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: 0.0000961

Gnomad4 NFE exome AF: 0.000193

Gnomad4 OTH exome AF: 0.000145

GnomAD4 genome AF: 0.000140 AC: 21 AN: 149790 Hom.: 0 Cov.: 33 AF XY: 0.000109 AC XY: 8 AN XY: 73130

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000298

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000367 Hom.: 0

Bravo AF: 0.000174

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 20, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 01, 2023	The c.49C>G (p.L17V) 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 49, causing the leucine (L) at amino acid position 17 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	0.082
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	14
DANN	Benign	0.69
DEOGEN2	Benign	0.018	T;.;T;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.75	.;T;T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.089	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.6	L;L;L;.
MutationTaster	Benign	0.94	N;N;N;N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.39	N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.56	T;T;T;T
Sift4G	Benign	0.10	T;T;T;T
Polyphen		0.0	B;B;B;.
Vest4		0.23
MutPred		0.49		Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);
MVP		0.17
MPC		0.62
ClinPred		0.030	T
GERP RS		1.5
Varity_R		0.048
gMVP		0.29

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

LitVar

Other links and lift over

dbSNP: rs797045802; hg19: chr11-64481123;