rs139264192

Variant names:

• chr11-64648804-G-C
• rs139264192
• NM_015080.4:c.3213C>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_015080.4(NRXN2):​c.3213C>G​(p.Leu1071Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00257 in 1,614,202 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (12 hom.)
• Consequence: NRXN2 NM_015080.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.711
• Publications: 5 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 11-64648804-G-C is Benign according to our data. Variant chr11-64648804-G-C is described in ClinVar as [Benign]. Clinvar id is 211705.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.711 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRXN2	NM_015080.4	c.3213C>G	p.Leu1071Leu	synonymous_variant	Exon 16 of 23	ENST00000265459.11	NP_055895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRXN2	ENST00000265459.11	c.3213C>G	p.Leu1071Leu	synonymous_variant	Exon 16 of 23	5	NM_015080.4	ENSP00000265459.5
NRXN2	ENST00000704782.1	c.3222C>G	p.Leu1074Leu	synonymous_variant	Exon 15 of 22			ENSP00000516031.1
NRXN2	ENST00000704781.1	c.3222C>G	p.Leu1074Leu	synonymous_variant	Exon 15 of 22			ENSP00000516029.1

Frequencies

GnomAD3 genomes AF: 0.00198 AC: 301 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00297

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00231 AC: 582 AN: 251458 AF XY: 0.00233

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.00333

Gnomad NFE exome AF: 0.00324

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00263 AC: 3846 AN: 1461884 Hom.: 12 Cov.: 32 AF XY: 0.00254 AC XY: 1849 AN XY: 727244

African (AFR) AF: 0.000418 AC: 14 AN: 33480

American (AMR) AF: 0.000827 AC: 37 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000842 AC: 22 AN: 26136

East Asian (EAS) AF: 0.000756 AC: 30 AN: 39700

South Asian (SAS) AF: 0.00265 AC: 229 AN: 86258

European-Finnish (FIN) AF: 0.00352 AC: 188 AN: 53418

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00287 AC: 3190 AN: 1112006

Other (OTH) AF: 0.00222 AC: 134 AN: 60396

GnomAD4 genome AF: 0.00198 AC: 301 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.00185 AC XY: 138 AN XY: 74488

African (AFR) AF: 0.000265 AC: 11 AN: 41570

American (AMR) AF: 0.00268 AC: 41 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5184

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4832

European-Finnish (FIN) AF: 0.00254 AC: 27 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00297 AC: 202 AN: 68016

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00250 Hom.: 0

Bravo AF: 0.00182

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00229

EpiControl AF: 0.00172

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 13, 2015

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

NRXN2-related disorder Benign:1

Nov 16, 2019

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
BayesDel_noAF	Benign	-0.53
CADD	Benign	11
DANN	Benign	0.81
PhyloP100		0.71
Mutation Taster		=74/26	polymorphism

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

Other links and lift over

dbSNP: rs139264192; hg19: chr11-64416276;