chr11-64673448-T-C

Variant names:

• chr11-64673448-T-C
• rs506338
• NM_015080.4:c.1197+3545A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015080.4(NRXN2):​c.1197+3545A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.517 in 152,056 control chromosomes in the GnomAD database, including 23,762 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.52 (23762 hom., cov: 31)
• Consequence: NRXN2 NM_015080.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.144
• Publications: 30 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 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.692 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRXN2	NM_015080.4	c.1197+3545A>G		intron_variant	Intron 7 of 22	ENST00000265459.11	NP_055895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRXN2	ENST00000265459.11	c.1197+3545A>G		intron_variant	Intron 7 of 22	5	NM_015080.4	ENSP00000265459.5
NRXN2	ENST00000704782.1	c.1197+3545A>G		intron_variant	Intron 6 of 21			ENSP00000516031.1
NRXN2	ENST00000704781.1	c.1197+3545A>G		intron_variant	Intron 6 of 21			ENSP00000516029.1

Frequencies

GnomAD3 genomes AF: 0.517 AC: 78543 AN: 151938 Hom.: 23765 Cov.: 31

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.840

Gnomad AMR AF: 0.504

Gnomad ASJ AF: 0.681

Gnomad EAS AF: 0.225

Gnomad SAS AF: 0.586

Gnomad FIN AF: 0.575

Gnomad MID AF: 0.655

Gnomad NFE AF: 0.697

Gnomad OTH AF: 0.559

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.517 AC: 78559 AN: 152056 Hom.: 23762 Cov.: 31 AF XY: 0.510 AC XY: 37910 AN XY: 74310

African (AFR) AF: 0.214 AC: 8896 AN: 41480

American (AMR) AF: 0.504 AC: 7700 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.681 AC: 2363 AN: 3470

East Asian (EAS) AF: 0.225 AC: 1166 AN: 5172

South Asian (SAS) AF: 0.586 AC: 2821 AN: 4816

European-Finnish (FIN) AF: 0.575 AC: 6066 AN: 10546

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.697 AC: 47406 AN: 67980

Other (OTH) AF: 0.561 AC: 1182 AN: 2108

Alfa AF: 0.625 Hom.: 58274

Bravo AF: 0.498

Asia WGS AF: 0.389 AC: 1354 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.6
DANN	Benign	0.79
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs506338; hg19: chr11-64440920;